Monitoring device and monitoring method

ABSTRACT

A monitoring device which measures numerical value information on a subject substance in a body fluid has an electrochemical sensor including a sensor unit for detecting the subject substance which is used in the way of being embedded subcutaneously and generating an electric signal correlating to the numerical value information on the subject substance, and a temperature control unit which adjusts the detected ambient temperature as a temperature ambient to a sensor unit when detecting the subject substance so as to reach a target setting temperature when measuring the subject substance.

The disclosures of Japanese patent applications No. JP2010-009472 filedon Jan. 19, 2010 and No. JP2010-272492 filed on Dec. 7, 2010 includingthe specification, drawings and abstract are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a monitoring device for and amonitoring method of measuring numerical value information on a subjectsubstance in a body fluid.

BACKGROUND OF THE INVENTION

A conventional known technology is a technology of measuring thenumerical value information on the subject substance in the body fluid,e.g., measuring continuously a glucose concentration in an interstitialliquid of the examinee by employing an electrochemical sensor embeddedin an abdomen region and an arm region of the examinee. Theelectrochemical sensor is a sensor capable of detecting a minute amountof electric current by making use of electrochemical reaction, and issuited to detecting a minute amount of chemical substance in whichoxidation-reduction reaction occurs.

The electrochemical sensor for measuring the glucose concentrationinvolves using, in many cases, a biosensor which detects the subjectsubstance by utilizing enzyme reaction in a way that immobilizes theenzyme to a sensor unit so disposed as to be embedded subcutaneously.This type of biosensor normally has a working electrode and a counterelectrode, in which the enzyme (e.g., glucose oxidase) is immobilized tothe working electrode. The glucose concentration can be measured basedon, with a constant voltage (e.g., approximately 0.3V-0.6V) beingconsecutively applied to between the working electrode and the counterelectrode, a response current obtained at this point of time.

The glucose oxidase produces gluconic acid by selectively reacting onthe glucose under an existence of oxygen. On this occasion, the oxygenis reduced, while hydrogen peroxide proportional to a quantity of theglucose is generated. The hydrogen peroxide can be oxidizedelectrochemically easily and can be therefore measured by use of a pairof electrodes. Namely, the response current value can be obtained by theelectrochemically oxidizing the hydrogen peroxide generated by theenzyme reaction of the enzyme as described above. Then, the glucoseconcentration can be calculated based on a sampling current obtained byperiodically sampling the electric current from the continuouslyacquired response current values.

An activity of the enzyme, however, fluctuates depending on a reactiontemperature. By contrast, a subcutaneous temperature largely fluctuatesdepending on a change in heat up temperature environment surrounding theexaminee such as a living environment (e.g., an outdoor air temperature)of the examinee and activities in daily living (typified by bathing andtaking excises) thereof. Therefore, in the case of continuouslymeasuring the glucose concentration over a comparatively long period oftime by use of the subcutaneous-embedding type of electrochemicalsensor, a measurement result thereof is easily affected particularly bythe change in heat up temperature environment.

Hence, in the case of measuring the glucose concentration by employingthe subcutaneous-embedding type of electrochemical sensor, there isproposed a technology of measuring a temperature ambient to the sensorunit as the reaction temperature and correcting a calculated valuecorresponding to the measured temperature (refer to U.S. Pat. No.6,560,471).

This type of temperature correction is normally conducted by use oftemperature correction data indicating temperature dependency that isempirically obtained beforehand. The temperature correction data is usedfor determining a correction quantity and a correction coefficient onthe basis of a temperature difference between a normal temperature andan ambient temperature in a way that sets the normal temperature (e.g.,about 25° C.) as a reference temperature and for canceling the influencecaused by the change in heat up temperature environment surrounding theexaminee on the basis of this correction quantity.

SUMMARY OF THE INVENTION

As by the prior art, however, in the case of correcting the measurementvalue obtained from the electrochemical sensor by use of, e.g., atemperature correction algorithm, this temperature correction algorithmbecomes highly complicated in many cases, accurate cancellation of theinfluence accompanying the fluctuation in the heat up temperatureenvironment when performing the measurement involves a difficulty.Hence, according to the prior art, there exist actual circumstances inwhich it is difficult to sufficiently enhance reliability andreproducibility of the measurement result of the subject substance.

It is an object of the present invention, which was devised under theactual circumstances described above, to provide a technology capable ofobtaining the measurement result exhibiting the high reliability and thehigh reproducibility under a state where a change in heat up temperatureenvironment occurs on the occasion of measuring numerical valueinformation on a subject substance in a body fluid.

The following means is adopted for accomplishing the object describedabove. A monitoring device according to the present invention, whichmeasures numerical value information on a subject substance in a bodyfluid, includes: an electrochemical sensor including a sensor unit fordetecting the subject substance which is used in the way of beingembedded subcutaneously and generating an electric signal correlating tothe numerical value information on the subject substance; and atemperature control unit including a temperature sensor which measures atemperature (this temperature contains a “detected ambient temperature”itself) correlating to a detected ambient temperature defined as atemperature ambient to the sensor unit and a temperature adjustingelement which adjusts the detected ambient temperature, and adjustingthe detected ambient temperature so as to reach a target settingtemperature when measuring the subject substance by controlling anoperation state of the temperature adjusting element on the basis of thetemperature measured by the temperature sensor.

As described above, the electrochemical sensor according to the presentinvention is disposed in such a way that the sensor unit for detectingthe subject substance is embedded subcutaneously. This sensor unit isformed on a part of, e.g. a base material and may retain a livingorganism based material such as the enzyme causing the enzyme reactionwith the subject substance. The electrochemical sensor may be used in amode where the sensor unit is disposed subcutaneously, and, as a matterof course, the whole electrochemical sensor including the base materialdoes not need disposing subcutaneously. Accordingly, for instance, thesensor unit is formed on a front end side of the base material, in whichcase a proximal end of the base material may be so disposed as to beexposed from the surface of the skin.

Further, the subject substance in the body fluid can be exemplified suchas glucose and lactic acid. Then, the numerical value information on thesubject substance has a concept of embracing the numerical valueinformation for quantitatively evaluating the subject substance such asmeasuring a concentration and a quantity of the subject substance and,in addition, the numerical value information for evaluating the subjectsubstance qualitatively such as detecting whether or not the subjectsubstance exists within a detection target region or exceeds a certainlevel.

According to the present invention, when detecting the subjectsubstance, the temperature control unit adjusts the detected ambienttemperature defined as the temperature ambient to the sensor unit so asto reach the target setting temperature. This target setting temperaturehas a role as the target temperature of the detected ambient temperaturewhen the sensor unit detects the subject substance and is a temperatureconsidered so that its influence is not exerted on the measurementresult even when the heat up temperature environment fluctuates as theexternal ambient temperature fluctuates so far as the subject substanceis measured in a state where the detected ambient temperature is kept inthe vicinity of this temperature. The target setting temperature can bepreviously set within a range of, e.g., the normal temperature. Notethat in the case of continuously measuring the subject substancerepeatedly at an interval of a fixed period of time by way of oneexample of the mode of using the electrochemical sensor, the measurementperiod and the measurement standby period of the subject substance occuralternately, thereby forming the measurement cycle. According to thepresent invention, at least during the measurement period of the subjectsubstance, the detected ambient temperature may be controlled to thetarget setting temperature. Namely, the detected ambient temperatureduring the measurement standby period of the subject substance may be ormay not be coincident with the target setting temperature.

According to the present invention, under a state where the heat uptemperature environment changes also, on the occasion of measuring thenumerical value information on the subject substance in the body fluid,the detected ambient temperature can be kept at a temperature equal tothe target setting temperature or at a temperature that is sufficientlyapproximate to the target setting temperature. Namely, the detectedambient temperature is maintained at the temperature equal to the targetsetting temperature, in which state the subject substance can bedetected. Therefore, for example, even when the heat up temperatureenvironment surrounding the examinee changes, it is feasible to restrainthe influence thereof from being exerted on the measurement result.Furthermore, according to the present invention, the electric signal(e.g., a value of a response current flowing to between electrodes ofthe sensor unit) correlating to the numerical value information on thesubject substance that is generated by the electrochemical sensor doesnot need undergoing a temperature correction process corresponding tothe heat up temperature environment when performing the measurement.Accordingly, even under the state where the heat up temperatureenvironment changes, it is possible to preferably improve thereliability and the reproducibility of the measurement result of thenumerical value information on the subject substance in the body fluid.

The monitoring device according to the present invention can be attachedto the examinee. Further, this temperature adjusting element may also bea Peltier device. The Peltier device is one type of a thermoelectrictransducer (material), in which when inverting a polarity of theelectric current flowing to a closed circuit formed by joining two typesof conductors or semiconductors, a relation between an exothermicportion and an endothermic portion is reversed. The operation state ofthe temperature adjusting element is controlled corresponding to themeasurement result of the temperature measured by the temperaturesensor, whereby the detected ambient temperature can be kept at thetarget setting temperature with high accuracy.

The monitoring device according to the present invention can furtherinclude a sensor control unit which controls the electrochemical sensor.In this case, each of the temperature sensor, the temperature adjustingelement and the temperature control unit may be disposed in a housingaccommodating the sensor control unit or in the electrochemical sensor.Moreover, the sensor control unit may further calculate numerical valueinformation on the subject substance on the basis of an electric signalgenerated by the electrochemical sensor.

Moreover, the monitoring device can further include a result displayunit for acquiring the calculation result of the sensor control unit anddisplaying the calculation result. In this case, each of the temperaturesensor, the temperature adjusting element and the temperature controlunit may be disposed in at least any one of the housing accommodatingthe sensor control unit, the electrochemical sensor and the housingprovided with the result display unit. Further, the subject substance inthe body fluid is the interstitial liquid or the glucose in the blood,and the monitoring device can measure the concentration of the glucose.

Moreover, the temperature control unit may adjust the detected ambienttemperature so as to reach a standby target setting temperature that isset lower than the target setting temperature when standing by formeasuring the subject substance.

Further, the temperature control unit may acquire first numerical valueinformation defined as the numerical value information on the subjectsubstance measured by use of the electrochemical sensor and secondnumerical value information defined as the numerical value informationon the subject substance measured by a second monitoring device in a waythat uses a body fluid sampled in vitro from an examinee, and maychange, if a difference between the first numerical value informationand the second numerical value information exceeds a predetermined firstthreshold value, a setting value of the target setting temperature whenmeasuring the subject substance.

Still further, the temperature control unit, in the case of adjustingthe detected ambient temperature so as to reach the standby targetsetting temperature when standing by for measuring the subjectsubstance, may acquire the first numerical value information and thesecond numerical value information, and may change, if the differencebetween the first numerical value information and the second numericalvalue information exceeds a predetermined second threshold value, thesetting value of the standby target setting temperature, on alow-temperature side, when standing by for measuring the subjectsubstance.

Yet further, the temperature control unit may acquire, with respect tothe first numerical value information and the second numerical valueinformation, each of the numerical value information corresponding tofirst timing after the monitoring device has started the measurement andthe numerical value information corresponding to second timing thattraces back to just a predetermined period from the first timing. Then,the temperature control unit may change, if a difference between thesecond numerical value information at the first timing and the secondnumerical value information at the second timing is within apredetermined third threshold value and if a difference between thefirst numerical value information at the first timing and the firstnumerical value information at the second timing exceeds a predeterminedfourth threshold value, the setting value of the target settingtemperature when measuring the subject substance.

Moreover, the temperature control unit may change, in the case ofadjusting the detected ambient temperature so as to reach the standbytarget setting temperature when standing by for measuring the subjectsubstance and if an elapse period reaching the first timing since thestart of the measurement exceeds a predetermined reference period, thesetting value of the standby target setting temperature, on thelow-temperature side, when standing by for measuring the subjectsubstance.

Further, the present invention can be grasped by way of a monitoringsystem which measures the numerical value information on the subjectsubstance, a monitoring method of measuring the numerical valueinformation on the subject substance, a program and a recording mediumrecorded with this program.

Herein, a monitoring method according to the present invention by whicha monitoring device having an electrochemical sensor including a sensorunit, for detecting a subject substance in a body fluid, disposed in theway of being embedded subcutaneously, measures numerical valueinformation on the subject substance, includes a step of adjusting adetected ambient temperature defined as a temperature ambient to thesensor unit so as to reach a target setting temperature when measuringthe subject substance.

Then, the monitoring method according to the present invention mayfurther include: a temperature acquiring step of acquiring a measurementresult of a temperature sensor which measures a temperature correlatingto the detected ambient temperature defined as the temperature ambientto the sensor unit when measuring the subject substance; a determiningstep of comparing the acquired temperature acquired in the temperatureacquiring step with a target setting temperature and determining whethera temperature difference between the acquired temperature and the targetsetting temperature is within a specified range or not; and a controlstep of controlling, when determining in the determining step that thetemperature difference exceeds the specified range, an operation stateof a temperature adjusting element for adjusting the detected ambienttemperature so as to get approximate to the target setting temperature,wherein the detected ambient temperature when detecting the subjectsubstance is adjusted, and the monitoring method may further include acalculation step of calculating, when determining in the determiningstep that the temperature difference between the acquired temperatureand the target setting temperature is within the specified range,numerical value information on the subject substance on the basis of anelectric signal generated by the electrochemical sensor. Further, themonitoring method according to the present invention can further includea result displaying step of displaying a calculated result in thecalculation step on a result display unit.

Furthermore, in the monitoring method according to the presentinvention, the detected ambient temperature may be adjusted so as toreach a standby target setting temperature that is set lower than thetarget setting temperature when standing by for measuring the subjectsubstance.

Further, in the monitoring method according to the present invention,first numerical value information defined as the numerical valueinformation on the subject substance calculated in the calculation stepand second numerical value information defined as the numerical valueinformation on the subject substance measured in a way that uses a bodyfluid sampled in vitro from an examinee may be acquired, and, if adifference between the first numerical value information and the secondnumerical value information exceeds a predetermined first thresholdvalue, a setting value of the target setting temperature when measuringthe subject substance may be changed.

Still further, in the monitoring method according to the presentinvention, in the case of adjusting the detected ambient temperature soas to reach the standby target setting temperature when standing by formeasuring the subject substance, the first numerical value informationand the second numerical value information may be acquired, and, if thedifference between the first numerical value information and the secondnumerical value information exceeds a predetermined second thresholdvalue, the setting value of the standby target setting temperature whenstanding by for measuring the subject substance may be changed on alow-temperature side.

Yet further, in the monitoring method according to the presentinvention, with respect to the first numerical value information and thesecond numerical value information, there may be acquired each of thenumerical value information corresponding to first timing after themonitoring device has started the measurement and the numerical valueinformation corresponding to second timing that traces back to just apredetermined period from the first timing. Then, if a differencebetween the second numerical value information at the first timing andthe second numerical value information at the second timing is within apredetermined third threshold value and if a difference between thefirst numerical value information at the first timing and the firstnumerical value information at the second timing exceeds a predeterminedfourth threshold value, the setting value of the target settingtemperature when measuring the subject substance may be changed.Moreover, in the monitoring method according to the present invention,in the case of adjusting the detected ambient temperature when standingby for measuring the subject substance so as to reach the standby targetsetting temperature, if an elapse period reaching the first timing sincethe start of the measurement exceeds a predetermined reference period,the setting value of the standby target setting temperature whenstanding by for measuring the subject substance may be changed on thelow-temperature side.

Moreover, a monitoring system according to the present invention, whichmeasures numerical value information on a subject substance in a bodyfluid, can include: a monitoring device having an electrochemical sensorincluding a sensor unit for detecting the subject substance which isused in the way of being embedded subcutaneously and generating anelectric signal correlating to the numerical value information on thesubject substance, a sensor control unit for controlling theelectrochemical sensor and calculating the numerical value informationon the subject substance on the basis of the electric signal generatedby the electrochemical sensor, and a temperature control unit whichadjusts the detected ambient temperature defined as a temperatureambient to the sensor unit so as to reach a target setting temperaturewhen measuring the subject substance; and a result display device forobtaining a calculated result of the sensor control unit and displayingthe calculated result.

In the monitoring system, the monitoring device can be attached to theexaminee. Moreover, the monitoring system can further include atemperature sensor which measures the temperature correlating to thedetected ambient temperature and a temperature adjusting element whichadjusts the detected ambient temperature. Then, the temperature controlunit can control an operation state of the temperature adjusting elementon the basis of the temperature measured by the temperature sensor.

Further, each of the temperature sensor, the temperature adjustingelement and the temperature control unit may be disposed in a housingaccommodating the sensor control unit or in the electrochemical sensor.As a matter of course, each of the temperature sensor, the temperatureadjusting element and the temperature control unit may also be disposedin at least any one of the housing accommodating the sensor controlunit, the electrochemical sensor and the housing provided with theresult display device.

Moreover, in the monitoring system, the temperature control unit mayadjust the detected ambient temperature when standing by for measuringthe subject substance so as to reach the standby target settingtemperature set lower than the target setting temperature.

Further, in the monitoring system, the temperature control unit mayacquire first numerical value information defined as the numerical valueinformation on the subject substance calculated by the sensor controlunit and second numerical value information defined as the numericalvalue information on the subject substance measured by a secondmonitoring device in a way that uses a body fluid sampled in vitro froman examinee, and may change, if a difference between the first numericalvalue information and the second numerical value information exceeds apredetermined first threshold value, a setting value of the targetsetting temperature when measuring the subject substance.

Moreover, in the monitoring system, the temperature control unit, in thecase of adjusting the detected ambient temperature so as to reach thestandby target setting temperature when standing by for measuring thesubject substance, may acquire the first numerical value information andthe second numerical value information, and may change, if thedifference between the first numerical value information and the secondnumerical value information exceeds a predetermined second thresholdvalue, the setting value of the standby target setting temperature, on alow-temperature side, when standing by for measuring the subjectsubstance.

Furthermore, in the monitoring system, the temperature control unit mayacquire, with respect to the first numerical value information and thesecond numerical value information, each of the numerical valueinformation corresponding to first timing after the monitoring devicehas started the measurement and the numerical value informationcorresponding to second timing that traces back to just a predeterminedperiod from the first timing. Then, the temperature control unit maychange, if a difference between the second numerical value informationat the first timing and the second numerical value information at thesecond timing is within a predetermined third threshold value and if adifference between the first numerical value information at the firsttiming and the first numerical value information at the second timingexceeds a predetermined fourth threshold value, the setting value of thetarget setting temperature when measuring the subject substance.

Further, in the monitoring system, the temperature control unit maychange, in the case of adjusting the detected ambient temperature so asto reach the standby target setting temperature when standing by formeasuring the subject substance and if an elapse period reaching thefirst timing since the start of the measurement exceeds a predeterminedreference period, the setting value of the standby target settingtemperature, on the low-temperature side, when standing by for measuringthe subject substance.

Further, a program according to the present invention makes a computerfor measuring numerical value information on a subject substance by useof an electrochemical sensor having a sensor unit, for detecting thesubject substance in a body fluid, disposed in the way of being embeddedsubcutaneously, the program making the computer execute: a temperatureacquiring step of acquiring a measurement result of a temperature sensorwhich measures a temperature correlating to the detected ambienttemperature defined as the temperature ambient to the sensor unit; adetermining step of comparing the acquired temperature acquired in thetemperature acquiring step with a target setting temperature anddetermining whether a temperature difference between the acquiredtemperature and the target setting temperature is within a specifiedrange or not; and a control step of controlling, when determining in thedetermining step that the temperature difference exceeds the specifiedrange, an operation state of a temperature adjusting element foradjusting the detected ambient temperature so as to get approximate tothe target setting temperature. The computer is control computer forcontrolling any one of the monitoring device or the monitoring systemdescribed above.

The program according to the present invention can further make thecomputer execute a calculation step of calculating, when determining inthe determining step that the temperature difference is within thespecified range, numerical value information on the subject substance onthe basis of an electric signal generated by the electrochemical sensor.Further, the program according to the present invention can further makethe computer execute a result displaying step of displaying a calculatedresult in the calculation step on a result display unit.

Moreover, the program according to the present invention can furthermake the computer adjust the detected ambient temperature so as to reacha standby target setting temperature that is set lower than the targetsetting temperature when standing by for measuring the subjectsubstance.

Further, the program according to the present invention can further makethe computer acquire first numerical value information defined as thenumerical value information on the subject substance calculated in thecalculation step and second numerical value information defined as thenumerical value information on the subject substance measured in a waythat uses a body fluid sampled in vitro from an examinee, and change, ifa difference between the first numerical value information and thesecond numerical value information exceeds a predetermined firstthreshold value, a setting value of the target setting temperature whenmeasuring the subject substance.

Furthermore, the program according to the present invention can furthermake the computer, in the case of adjusting the detected ambienttemperature so as to reach the standby target setting temperature whenstanding by for measuring the subject substance, acquire the firstnumerical value information and the second numerical value information,and change, if the difference between the first numerical valueinformation and the second numerical value information exceeds apredetermined second threshold value, the setting value of the standbytarget setting temperature when standing by for measuring the subjectsubstance on a low-temperature side.

Moreover, the program according to the present invention can furthermake the computer, with respect to the first numerical value informationand the second numerical value information, acquire each of thenumerical value information corresponding to first timing after themonitoring device has started the measurement and the numerical valueinformation corresponding to second timing that traces back to just apredetermined period from the first timing, and, if a difference betweenthe second numerical value information at the first timing and thesecond numerical value information at the second timing is within apredetermined third threshold value and if a difference between thefirst numerical value information at the first timing and the firstnumerical value information at the second timing exceeds a predeterminedfourth threshold value, change the setting value of the target settingtemperature when measuring the subject substance.

Moreover, the program according to the present invention can furthermake the computer, in the case of adjusting the detected ambienttemperature when standing by for measuring the subject substance so asto reach the standby target setting temperature, if an elapse periodreaching the first timing since the start of the measurement exceeds apredetermined reference period, change the setting value of the standbytarget setting temperature when standing by for measuring the subjectsubstance on the low-temperature side.

Further, the present invention can be grasped as a readable-by-computerrecording medium recoded with the program. Moreover, the means foraccomplishing the object of the present invention can be combined to thegreatest possible degree.

According to the present invention, it is feasible to provide thetechnology capable of obtaining the measurement result exhibiting thehigh reliability and the high reproducibility under the state where thechange in heat up temperature environment occurs on the occasion ofmeasuring the numerical value information on the subject substance inthe body fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing an outline of a configuration of amonitoring device in a first working example.

FIG. 2 is a whole perspective view of a glucose sensor together with anenlarged view of a principal portion in the first working example.

FIG. 3 is a whole perspective view of the glucose sensor together withthe enlarged view of the principal portion in the first working example.

FIG. 4 is an explanatory conceptual diagram of a Peltier device in thefirst working example.

FIG. 5 is a block diagram of functions realized by a control computer ofthe monitoring device in the first working example.

FIG. 6 is a block diagram showing an outline of a configuration of atemperature control unit in the first working example.

FIG. 7 is a flowchart showing a control routine when the monitoringdevice measures a glucose concentration in the first working example.

FIG. 8 is an explanatory diagram illustrating positions where atemperature sensor, the Peltier device and a temperature control unitaccording to a second working example are disposed.

FIG. 9 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a third working example are disposed.

FIG. 10 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a modified example of the third working example aredisposed.

FIG. 11 is a diagram showing an outline of a configuration of themonitoring device according to a fourth working example.

FIG. 12 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a first modified example of the fourth working example aredisposed.

FIG. 13 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a second modified example of the fourth working example aredisposed.

FIG. 14 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a third modified example of the fourth working example aredisposed.

FIG. 15 is an explanatory diagram illustrating the positions where thetemperature sensor, the Peltier device and the temperature control unitaccording to a fourth modified example of the fourth working example aredisposed.

FIG. 16 is a diagram showing an outline of a configuration of themonitoring device according to a fifth working example.

FIG. 17 is a block diagram showing an outline of a configuration of thetemperature control unit according to the fifth working example.

FIG. 18 is a timing chart showing a measurement cycle of the glucoseconcentration in a sixth working example.

FIG. 19 is a flowchart showing a second control routine when themonitoring device measures the glucose concentration in the sixthworking example.

FIG. 20 is a diagram of an outline of a configuration of a secondmonitoring device.

FIG. 21 is a diagram of a functional configuration of the secondmonitoring device.

FIG. 22 is a flowchart showing a setting value adjustment controlroutine according to a seventh working example.

FIG. 23 is a flowchart showing a second setting value adjustment controlroutine according to the seventh working example.

FIG. 24 is a flowchart showing a setting value adjustment controlroutine according to an eighth working example.

FIG. 25 is a flowchart showing a second setting value adjustment controlroutine according to the eighth working example.

FIG. 26 is a flowchart showing a setting value adjustment controlroutine according to a ninth working example.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An in-depth description of a mode for carrying out the invention willhereinafter be described on an exemplifying and not-limiting basis withreference to the drawings. The embodiment will discuss a continuousglucose monitoring device attached to an examinee and thus employed byway of one example of a measuring device (monitoring device) accordingto the present invention. Note that the same components illustrated inthe drawings given above are marked with the same reference numerals andsymbols. Further, the descriptions of the respective embodiments of themeasuring device according to the present invention, which willhereinafter be discussed, serve also as the descriptions of theindividual embodiments of a measuring system, a measuring method, aprogram and a readable-by-computer recording medium recorded with theprogram.

First Working Example

FIG. 1 is a view illustrating an outline of a configuration of thecontinuous glucose monitoring (abbreviated to CGM) device (which willhereinafter simply be termed “the monitoring device” or “measuringdevice”) in a first working example. A monitoring device 1 is capable ofcontinuously measuring a glucose concentration in a blood and aninterstitial liquid. The monitoring device 1 can be used in the way ofbeing preferably attached to a skin of, e.g., an abdomen region and anarm region of a human body (examinee) but is not limited to this usagemode. This monitoring device 1 includes a housing 2, a control computer3 and an electrochemical sensor 4.

This electrochemical sensor 4 is a sensor which detects a specifiedsubject substance by making use of electrochemical sensor reaction. Theelectrochemical sensor 4 in the first working example is classified as aso-called biosensor. The biosensor is a sensor which measures anddetects the subject substance in a way that involves using a livingorganism or a material derived from the living organism as an element ofwhich the subject substance is recognized. The electrochemical sensor 4in the first working example is employed for measuring the glucoseconcentration in a body fluid and will therefore be referred to as a“glucose sensor”. Furthermore, the glucose in the body fluid correspondsto the “subject substance” according to the present invention, and theglucose concentration can be given as “numerical value information”related to the subject substance according to the present invention.

The housing 2 takes an external shape of the monitoring device 1 andincludes a cover 20 and a base plate 21. The cover 20 and the base plate21, which are fixed to each other, define the housing 2 accommodatingthe control computer 3. The housing 2 has, it is preferable, awaterproofing property or a water resisting property. In the housing 2such as this, e.g., at least the cover 20 (and the base plate 21 as thenecessity may arise) is composed of a material such as a metal and apolypropylene resin each exhibiting an extremely low water permeability.

The base plate 21 is a portion into which the glucose sensor 4 isinserted, and an end portion (which will hereinafter be termed a[proximal end]) 40 on the proximal side of the glucose sensor 4 isfixed. A bonding film 5 is fixed to the base plate 21. This bonding film5 is used when fixedly attaching (adhering) the continuous monitoringdevice 1 to the skin. The bonding film 5 can involve using adouble-sided adhesive tape.

The control computer 3 is mounted with electronic components requiredfor predetermined operations (such as applying a voltage, performingtemperature control of a detected ambient temperature that will bedescribed later on and calculating the glucose concentration) of themonitoring device 1. This control computer 3 further includes a terminal30 brought into contact with an electrode 42 (see FIG. 2) of the glucosesensor 4, which will be explained later on. This terminal 30 is employedfor acquiring a response current value from the glucose sensor 4 byapplying the voltage to the glucose sensor 4.

The glucose sensor 4 serves to acquire the response corresponding to theglucose concentration in the blood and the interstitial liquid. Thoughthe details will be described later on, a tip portion of the glucosesensor 4 is provided with an immobilized enzyme unit 43 as a sensor unitfor detecting the glucose in the blood and the interstitial liquid, andthis immobilized enzyme unit 43 is employed in the way of being at leastimplanted subcutaneously. Herein, the glucose sensor 4 is such that theproximal end 40 protrudes from the skin 6 and comes into contact withthe terminal 30 of the control computer 3, while a large proportion ofother units (including the immobilized enzyme unit 43) thereof areinserted into the skin 6.

FIGS. 2 and 3 are whole perspective views illustrated together with anenlarge view of the principal portion. As illustrated therein, theglucose sensor 4 has a base sheet 41, the electrode 42, the immobilizedenzyme unit 43 and a lead wire 44.

The base sheet 41 serves to support the electrode 42 and is formed in asheet-like shape exhibiting an insulating property and flexibility aswell. In the base sheet 41, an end portion 41A exists inside the housing2, while an end portion 41B is formed in an acute shape. Adoption of theacute structure of the end portion 41B facilitates the insertion of theglucose sensor 4 into the skin 6, thereby enabling a pain of the user(examinee) to be relieved. The end portion 41B is not, however, limitedto the specified shape but may take shapes other than the acute shape.

Usable materials for the base sheet 41 may be those having no harmfuleffect in the human body but the proper insulating property and areexemplified by thermoplastic resins such as polyethyleneterephthalate(PET), polypropylene (PP) and polyethylene (PE) and by thermosettingresins such as a polyimide resin and an epoxy resin.

The electrode 42 is used for applying the voltage to the immobilizedenzyme unit 43 and capturing the electrons from the immobilized enzymeunit 43. The electrode 42 includes a working electrode 42A and a counterelectrode 42B. The working electrode 42A is an electrode element fortransferring and receiving the electrons to and from the glucose. Thecounter electrode 42B is used for applying the voltage together with theworking electrode 42A. The electrode 42 can be produced based on ascreen printing technique using, e.g., a carbon ink.

The immobilized enzyme unit 43 serves as a medium for transferring andreceiving the electrons between the glucose and the working electrode42A. This immobilized enzyme unit 43 is formed by immobilizing a glucoseoxidoreductase to an end portion 42Aa of the working electrode 42A onone surface (which is herein an upper surface) of the base sheet 41. Theglucose oxidoreductase includes an electron-accepting region defined asa region for receiving the electrons derived from a substrate and anelectron-donating region defined as a region for donating the electronsderived from the substrate to the working electrode 42A.

The glucose oxidoreductase can involve using glucose oxidase (GOD) andglucose dehydrogenase (GDH). The glucose oxidoreductase involves usingpreferably the GDH and more preferably cytochrome GDH. The use of theGDH as the glucose oxidoreductase enables the electrons to be taken out(captured) from the glucose without producing any hydrogen peroxide. Itis therefore feasible to avoid damaging the glucose and somatic cells ofthe living organism by the hydrogen peroxide and to realize the glucosesensor 4 that is safer to the human body and exhibits high stabilitywith less of deterioration of the enzyme. A method of immobilizing theglucose oxidoreductase can involve adopting a variety of known methodssuch as a method of utilizing MPC (2-methacryloxyethylphosphorylcholine) polymer in which a silane coupling agent isintroduced into polymeric gel, high polymer such as polyacrylamide andphosphor and phospholipids polymer, or a protein membrane.

The lead wire 44 serves to transmit items of information measured by atemperature sensor 8 to the control computer 3. A large part of thislead wire 44 is formed on the undersurface (i.e., the surface formedwith none of the immobilized enzyme unit 43) of the base sheet 41 of theglucose sensor 4. One end of the lead wire 44 comes into contact withthe temperature sensor 8, while the other end is exposed from the uppersurface of the base sheet 41 of the glucose sensor 4.

The temperature sensor 8 is a sensor for measuring a detected ambienttemperature THs defined as a temperature ambient to the immobilizedenzyme unit 43 when the glucose sensor 4 detects the subject substance,i.e., the glucose. This temperature sensor 8 is provided in a positioncorresponding to the immobilized enzyme unit 43 on the undersurface ofthe base plate 41 of the glucose sensor 4 in a way that enables themeasurement of the temperature ambient to the immobilized enzyme unit 43of the glucose sensor 4, i.e., enables the measurement of a subcutaneoustemperature of the human body (examinee). The temperature sensor 8 isbrought into contact with the terminal 30 of the control computer 3 atthe end portion 44A via the lead wire 44. The temperature sensor 8 caninvolve using a variety of known sensors in addition to, e.g., athermistor.

Further, as illustrated in FIG. 1, the monitoring device 1 includes aPeltier element (Peltier device) 9 classified as one type ofthermoelectric transducers. The Peltier device 9 in the first workingexample is a temperature control device for controlling the detectedambient temperature THs as will be explained later on. FIG. 4 is anexplanatory conceptual diagram of the Peltier device in the firstworking example. As in the conceptual diagram illustrated therein, thePeltier device 9 has a closed circuit formed by establishing a P-Njunction of N- and P-type semiconductors and is configured to makeswitchable a polarity of an electric current flowing to the closedcircuit. Herein, one junction surface of the N- and P-typesemiconductors is referred to as a “first heat exchange surface 9A”, andthe other junction surface is referred to as a “second heat exchangesurface 9B”. Herein, the Peltier device 9 is disposed in such a positionthat the second heat exchange surface 9B faces the skin side of theexaminee, i.e., the [second heat exchange surface 9B] is closer to theskin than the first heat exchange surface 9A. Further, in the firstworking example, as illustrated in FIG. 1, a notched portion (a recessedportion or a cavity) is formed in the base plate 21, and the Peltierdevice 9 is set in this notched portion. This contrivance intends toefficiently transmit, down to a subcutaneous tissue, a heat uptemperature due to a heat radiation (exothermic) phenomenon or a cooldown temperature due to an endothermal phenomenon from the second heatexchange surface 9B.

In the thus-disposed Peltier device 9, when the electric current flowsto the P-N junction thereof, the endothermal phenomenon occurs at theN→P junction, while the heat radiation phenomenon occurs at the P→Njunction. In this drawing, a direction in which the electric currentflows in the illustrated arrowhead (→) direction is set as a “firstdirection”, and a reversed direction is set as a “second direction”.

Herein, as illustrated in FIG. 4, when the electric current flows in thefirst direction, the endothermal phenomenon occurs from the first heatexchange surface 9A, and the exothermic phenomenon occurs from thesecond heat exchange surface 9B. Namely, in this case, the heat absorbedfrom on the side of the first heat exchange surface 9A is radiated onthe side of the second heat exchange surface 9B, thereby heating theperipheral area of the second heat exchange surface 9B. Further, theperiphery of the first heat exchange surface 9A is cooled off by theendothermal action. On the other hand, in the case of inverting thepolarity of the electric current and causing the electric current toflow in the second direction, the endothermal phenomenon occurs from thesecond heat exchange surface 9B, while the exothermic phenomenon occursfrom the first heat exchange surface 9A. Accordingly, in this case, itfollows that the periphery of the second heat exchange surface 9B iscooled off, while the periphery of the first heat exchange surface 9A isheated up.

In the first working example, the second heat exchange surface 9B of thePeltier device 9 faces the skin side of the examinee, and hence the skinsurface is heated by flowing the electric current in the firstdirection. Then, the heat up temperature transmitted to the subcutaneoustissue, whereby the temperature ambient to the immobilized enzyme unit43 rises. On the other hand, the skin surface is cooled down this timeby flowing the electric current in the second direction while switchingover the polarity of the electric current, and the cool down temperatureis transmitted to the subcutaneous tissue, whereby the temperatureambient to the immobilized enzyme unit 43 descends. Thus, in the firstworking example, it is feasible to preferably control the temperatureambient to the immobilized enzyme unit 43.

Next, each of functions provided in the monitoring device 1 will bedescribed. FIG. 5 is a block diagram of the functions realized by thecontrol computer 3 of the monitoring device 1 in the first workingexample. The control computer 3 in the first working example is acomputer including a general purpose or dedicated processor whichcontrols the respective function units by processing instructions anddata, a ROM (Read Only Memory) stored with a variety of controlprograms, a RAM (Random Access Memory) on which the control programs aredeployed, a hard disk (Hard Disk) stored with various items of data usedby the monitoring device 1 as the necessity may arise, and so on. Theprocessor interprets and executes the control programs deployed on theRAM. These configurations may, including the processor, be individuallyprovided in the respective function units and may also be shared withthe respective function units.

A sensor control unit 12 realizes a function of controlling the varietyof operations such as setting voltage application timing, setting anapplied voltage value, sampling the response current, calculating theglucose concentration and performing the communications with externalinformation processing terminals according tote necessity. Thetemperature control unit 13 functions in cooperation with thetemperature sensor 8 and the Peltier device 9 in order to control thetemperature so that the detected ambient temperature THs becomes atarget setting temperature THtg when the glucose sensor 4 detects thesubject substance. The detected ambient temperature THs is thetemperature ambient to the immobilized enzyme unit 43. Further, thetarget setting temperature THtg will be described later on.

A communication unit 11 realizes the function of performing the datacommunications between the monitoring device and the externalinformation processing terminals. This communication unit 11 has atransmitting unit and includes a receiving unit as the case may arise.The data communications can involve utilizing a wireless communicationmeans (IrDA (Infrared Data Association) using infrared rays or Bluetoothemploying a frequency band of 2.4 GHz). As a matter of course, the wireddata communications may also be conducted via a cable between thecommunication unit 11 of the monitoring device 1 and the externalinformation processing terminals.

The external information processing terminals can be exemplified such asa display unit (a result display unit) for displaying a result ofmeasuring the glucose concentration, an insulin injecting device (e.g.,an insulin pump) for dosing the insulin to the human body, a simplifiedtype blood glucose level measuring device, an external personal computerand an alarm device. The alarm device is a device which informs apatient of individual states showing that the examinee comes toglucopenia or hyperglycemia or has a symptom of becoming the glucopeniaor the hyperglycemia on the basis of the data given from the monitoringdevice 1.

The data communications between the monitoring device 1 and the insulininjecting device are performed by transmitting, e.g., the glucoseconcentration measured result given from the monitoring device 1 to theinsulin injecting device. This scheme enables an insulin dosage, whichshould be given to the human body, to be controlled based on themeasured data sent transmitted from the monitoring device 1.

The data communications between the monitoring device 1 and thesimplified type blood glucose level measuring device are carried out bytransmitting, e.g., a blood glucose level measured result given from thesimplified type blood glucose level measuring device to the monitoringdevice 1. With this scheme, when the measured result of the monitoringdevice 1 is compared with the measured result of the simplified typeblood glucose level measuring device and if a gap between these measuredresults is equal to or larger than a fixed value, the monitoring device1 may be calibrated. The raw data (response current) measured by themonitoring device 1 may also be transmitted to the simplified type bloodglucose level measuring device.

The data communications between the monitoring device 1 and the displayunit are performed by transmitting, e.g., the glucose concentrationmeasured result given from the monitoring device 1 to the display unit.Note that the display unit may be used in a portable (attachable) modefor the examinee (which can be exemplified by a wrist watch type displaymachine and a portable type display machine attached to the skin surfacein the vicinity of the monitoring device 1) and may also be usedotherwise. Further, the display unit can be configured in such a modethat the display unit is formed integrally with the monitoring device 1in the way of being included as a part of the monitoring device 1. Thus,the display unit, to which the measured result of the monitoring device1 is transmitted, displays this measured result, thereby enabling theuser (examinee) to easily recognize and grasp the present blood glucoselevel.

The data communications between the monitoring device 1 and the personalcomputer are performed by transmitting, e.g., the blood glucose levelmeasured result and the raw data (response current) to the personalcomputer. This scheme enables a transition of the glucose concentrationto be monitored on the personal computer.

The storage unit 14 is a unit stored with programs and data required forthe variety of calculations (e.g., data about a working curve and dataabout a voltage application pattern). This storage unit 14 may also be aunit capable of storing the response current value and the calculatedglucose concentration given from the glucose sensor 4.

Next, an in-depth description of the temperature control unit 13 will bemade. Herein, the monitoring device 1 according to the first workingexample detects the glucose in the body fluid by making use of theenzyme reaction of the enzyme retained by the immobilized enzyme unit 43in the glucose sensor 4. Then, a continuous operation period of themonitoring device 1 covers, it is desirable, preferably several days andmore preferably one week through a few weeks.

Accordingly, during the operation period of the monitoring device 1, itfollows that the external heat up temperature environment around theexaminee momentarily changes. Namely, factors for fluctuations of thesubcutaneous temperature are a change in living environment (e.g., anoutdoor air temperature) and a case of engaging in activities in dailyliving typified by bathing, taking a shower and taking excises.

In this connection, the glucose oxidoreductase in the immobilized enzymeunit 43 fluctuates in enzyme activity due to the reaction temperature,and hence it is necessary to cancel influence of the change in heat uptemperature environment around the examinee. Such being the case, themonitoring device 1, when the glucose sensor 4 detects the glucose,conducts temperature adjustment control for adjusting the temperature sothat the detected ambient temperature THs defined as the temperatureambient to the immobilized enzyme unit 43 reaches the target settingtemperature THtg.

The target setting temperature THtg is a target temperature set whenadjusting the detected ambient temperature THs under the temperatureadjustment control and is, as far as the glucose concentration ismeasured in a status where the detected ambient temperature THs is keptin the vicinity of this target temperature, a temperature considered notto affect the measured result even when the heat up temperatureenvironment fluctuates. In the first working example, the target settingtemperature THtg is preset based on an empirical rule, within a rangeof, e.g., normal temperature.

The temperature adjustment control is realized by the temperaturecontrol unit 13 which controls the operation state of the Peltier device9 on the basis of the temperature measured by the temperature sensor 8.Herein, the temperature sensor 8 is connected to the temperature controlunit 13 via the lead wire 44, and the information measured by thetemperature sensor 8 is inputted to the temperature control unit 13 ofthe control computer 3. Further, the Peltier device 9 is electricallyconnected to the control computer 3, whereby the temperature controlunit 13 controls the operation state of the Peltier device 9.

Herein, an example of a configuration of the temperature control unit 13will hereinafter be described with reference to FIG. 6. In the exampleof the configuration in FIG. 6, the temperature control unit 13 isconfigured by including a temperature analyzing unit 13A, a power switchunit 13B and a current switching unit 13C. Further, the temperaturecontrol unit 13 is supplied with a direct current (DC) from a powersource 10. The power source 10 can involve adopting a button battery ofwhich a power voltage is on the order of 1V-3V but is not limited tothis type of battery. Moreover, the power source 10 can supply theelectric power to other function units (e.g., the sensor control unit12) of the control computer 3 and the glucose sensor 4.

The power switch unit 13B is an electronic component which switchesON/OFF the electric power supplied to the Peltier device 9. Further, thecurrent switching unit 13C is an electronic component capable ofinverting the polarity of the direct current supplied to the Peltierdevice 9 and switching over the current direction to any one of thefirst direction and the second direction. Moreover, the temperatureanalyzing unit 13A acquires the measured result of the detected ambienttemperature THs inputted from the temperature sensor 8 and determines,based on the result of the comparison with the target settingtemperature THtg, a content of the control with respect to the Peltierdevice 9.

FIG. 7 is a flowchart illustrating a processing flow when the continuousglucose monitoring device measures the glucose concentration. When thepower source of the monitoring device 1 is in an ON-state, the controlcomputer 3 deploys, on the RAM, the control program stored in the ROM,and the processor executes the control program at an interval of a fixedperiod of time, thereby realizing the respective processes in theflowchart. Namely, the individual functions provided in the controlcomputer 3 explained in FIG. 5 are actualized in such a way that theprocessor of the control computer 3 cooperates with the control programstored in the ROM.

When starting the execution of the control program, to begin with, instep S101, the temperature control unit 13 acquires the detected ambienttemperature THs based on an output signal of the temperature sensor 8.Herein, the temperature sensor 8 measures the detected ambienttemperature THs at the interval of executing the control program, i.e.,at the interval of the predetermined fixed period of time, and themeasurement data thereof is inputted to the temperature analyzing unit13A of the temperature control unit 13. Step S101 in the flowchartcorresponds to a temperature acquiring step according to a measurementmethod of the present invention.

In step S102, the temperature analyzing unit 13A of the temperaturecontrol unit 13 compares the acquired detected ambient temperature THswith the target setting temperature THtg. Then, it is determined whetheror not an absolute value of a difference between the detected ambienttemperature THs and the target setting temperature THtg falls within arange of a specified temperature difference ΔTHsh. If determined to beaffirmative in this step (|THs−THtg|≦ΔTHsh), the detected ambienttemperature THs can be deemed to be coincident with the target settingtemperature THtg or to be sufficiently approximate to the target settingtemperature THtg. In this case, even when the detected ambienttemperature THs is not adjusted more elaborately than this, it isconsidered that the enzyme activity of the enzyme immobilized by theimmobilized enzyme unit 43 has no variation as affected by the externalambient temperature. Namely, if the glucose concentration is measured inthis state, it is determined that there is no possibility that ameasurement error might occur due to the fluctuations of the externalambient temperature, and the operation proceeds to step S103.

In step S103, when the power switch unit 13B is kept ON, the powerswitch unit 13B is switched OFF and, as a result, the power supply tothe Peltier device 9 is stopped. Namely, the operation of the Peltierdevice 9 is stopped. Note that the power switch unit 13B remains OFFfrom the beginning, the operation may proceed directly to next stepS104.

In step S104, it is determined whether the should-be-measured timing(measurement request timing) of the glucose concentration is reached atthe present or not. A contrivance in the monitoring device 1 accordingto the first working example is that the glucose concentration isautomatically measured, e.g., at the preset interval (e.g., at such afrequency that the measurement may be conducted once for severalminutes) or at the predetermined timing. As a matter of course, alsowhen the user (examinee) gives a manual measurement request (such aspressing a measurement start button), the glucose concentration can bemeasured separately. The timing is determined to be the measurementtiming of the glucose concentration in this step, in which case theoperation proceeds to step S105, but, whereas if not so, the executionof the present control program is temporarily terminated.

In step S105, the sensor control unit 12 applies the voltage to betweenthe electrodes 42 (between the working electrode 42A and the counterelectrode 42B) of the glucose sensor 4. As a result, the glucose in thebody fluid is reduced (the electrons are captured) by the oxidoreductaseof the immobilized enzyme unit 43, and the electrons thereof aresupplied to the working electrode via an electron supplying region.Then, a quantity of the electrons supplied to the working electrode 42Ais measured as a response current value. Subsequently, the glucosesensor 4 generates an electric signal which indicates the responsecurrent value when the voltage is applied, and the electric signal isoutput to the sensor control unit 12. The electric signal indicating theresponse current value is an electric signal having a correlation withthe concentration of the glucose defined as the subject substance. Thesensor control unit 12 receiving the electric signal inputted from theglucose sensor 4 calculates, based on the response current value, theglucose concentration (blood glucose level). When calculating theglucose concentration herein, there is no necessity for making thetemperature correction corresponding to the external ambienttemperature. As discussed above, in the present step, the sensor controlunit 12 controlling the glucose sensor 4 calculates the glucoseconcentration on the basis of the electric signal generated by theglucose sensor 4. Then, step S105 in this flowchart corresponds to acalculating step according to the measurement method of the presentinvention.

Furthermore, the communication unit 11 outputs the calculated result ofthe glucose concentration to the display unit, and the display unitdisplays the acquired measured result (calculated result) of the glucoseconcentration. Through this display, the examinee (user) is informed ofthe measured result of the glucose concentration. Moreover, thecalculated result of the glucose concentration may also be transmittedto other external information terminals. Upon finishing the process inthis step, the execution of the control program is temporarilyterminated.

Given next is a description of a case in which the absolute value of thedifference between the detected ambient temperature THs and the targetsetting temperature THtg does not fall within the range of the specifiedtemperature difference ΔTHsh (|THs−THtg|>ΔTHsh) in step S102. This caseis, it follows, applicable to that the detected ambient temperature THsis lower to some degree than the target setting temperature THtg or thatTHs is conversely higher to some degree than the target settingtemperature THtg.

Then, in this case, the operation proceeds to step S106, in which thetemperature control unit 13 determines whether or not the detectedambient temperature THs is lower than the target setting temperatureTHtg. Herein, if determined to be affirmative (THs<THtg), thetemperature control unit 13 determines it necessary to increase thedetected ambient temperature THs, and the operation proceeds to stepS107. Whereas if determined to be negative, the temperature control unit13 determines it necessary to decrease the detected ambient temperatureTHs, and the operation proceeds to step S108. Herein, the process instep S102 corresponds to a determining step according to the measurementmethod of the present invention.

In step S107, the temperature control unit 13, when the power switchunit 13B is in the OFF state, switches OFF this unit 13B, andsimultaneously controls the current switching unit 13C so that thedirection of the direct current supplied to the Peltier device 9 isswitched over to the first direction. The skin in the vicinity of thePeltier device 9 is thereby heated. Herein, the immobilized enzyme unit43 of the glucose sensor 4 is normally embedded to a depth on the orderof several millimeters (mm) at the deepest from the skin, and thePeltier device 9 heats up the skin surface, whereby the heat thereof canbe sufficiently propagated to the region in the vicinity of theimmobilized enzyme unit 43. As a result, the detected ambienttemperature THs can be raised up to the target setting temperature THtg,preferably.

Note that herein the number of the semiconductors configuring thePeltier device 9, a magnitude of the value of the electric current to besupplied and, for others, a physical property value related to thePeltier device 9 are designed within a proper range so as not toexcessively increase or decrease a changing speed (which is herein arising speed) of the detected ambient temperature THs. This is similarlyapplied to the case of supplying the electric current in the seconddirection to the Peltier device 9 and decreasing the detected ambienttemperature THs. Upon finishing the process in this step, the executionof the control program is temporarily terminated.

In step S108, the temperature control unit 13, when the power switchunit 13B is in the OFF state, switches ON this unit 13B, andsimultaneously controls the current switching unit 13C so that thedirection of the direct current supplied to the Peltier device 9 isswitched over to the second direction. The endothermal phenomenonthereby occurs from the skin in the vicinity of the Peltier device 9,thus cooling the skin surface. Then, this cool down temperature issufficiently propagated to the region vicinal to the immobilized enzymeunit 43, and hence the detected ambient temperature THs can bepreferably lowered down to the target setting temperature THtg. Uponfinishing the process in this step, the execution of the control programis temporarily terminated. The processes in steps S107 and S108 in thepresent flowchart correspond to a control step according to themeasurement method of the present invention.

The control program described above is executed iteratively on theper-fixed-time basis. Therefore, for example, the process related tostep S107 or S108 continues till the affirmative determination is madein step S102 from next time onward. Hence, according to the temperatureadjustment control in the first working example, after maintaining sucha temperature that the detected ambient temperature THs gets coincidentwith the target setting temperature THtg or a temperature that issufficiently approximate to the target setting temperature THtg, e.g.,the temperature deemed to be equal to the target setting temperatureTHtg, the glucose concentration can be measured. Further, as for theglucose concentration measurement method according to the first workingexample, the temperature is adjusted so that the detected ambienttemperature THs given when detecting the glucose defined as the subjectsubstance reaches the target setting temperature THtg.

According to the temperature adjustment control in the first workingexample, even under the state where the external heat up temperatureenvironment around the examinee changes, on the occasion of measuringthe glucose concentration, it is feasible to preferably restrain thechange in heat up temperature environment from adversely affecting themeasured result of the subject substance. Moreover, according to thepresent control, the electric signal generated by the glucose sensor 4does not need undergoing the temperature-correction corresponding to theheat up temperature environment at that point of time. It is thereforepossible to amply enhance reliability and reproducibility with respectto the measured result of the monitoring device 1.

It should be noted that the present invention can be grasped as acontrol program for making the control computer 3 execute the respectiveprocesses explained in FIG. 7, i.e., a program for realizing therespective functions of the control computer 3 or a readable-by-computerrecording medium recorded with this program. These functions can beprovided by making the computer read and execute the program on therecording medium. Herein, the readable-by-computer recording mediumconnotes a recording medium capable of storing information such as dataand programs electrically, magnetically, optically, mechanically or bychemical action, which can be read from the computer etc. Among theserecording mediums, for example, a flexible disc, a magneto-optic disc, aCD-ROM, a CD-R/W, a DVD, a DAT, an 8 mm tape, a memory card, etc aregiven as those removable from the computer. Further, a hard disc, a ROM(Read-Only Memory), etc are given as the recording mediums fixed withinthe computer.

Second Working Example

Herein, a second working example will be described with reference toFIG. 8. FIG. 8 is an explanatory diagram for illustrating layoutpositions of the temperature sensor 8, the Peltier device 9 and thetemperature control unit 13 according to the second working example. Thesecond working example is common to the first working example except apoint that the layout positions of the respective components aredifferent from those in the first working example. The discussion willbe focused on the different point from the already-described workingexample, and the explanations of the common points are omitted.

In the layout example illustrated in FIG. 1, the temperature controlunit 13 and the Peltier device 9 are disposed in the housing 2 whichaccommodates the control computer 3, and the temperature sensor 8 isdisposed in the glucose sensor 4. Note that the housing 2 can be said tobe, in other words, the housing 2 which accommodates the sensor controlunit 12. In the second working example, the Peltier device 9 is alsodisposed on the base sheet 41 of the glucose sensor 4. Note that, asillustrated in FIG. 8, the layout positions of the temperature sensor 8and the temperature control unit 13 are the same as in the example ofFIG. 1. A reason why the numeral 3 is attached with the numeral 13 putin parentheses is that the temperature control unit 13 in the secondworking example is, as already discussed in the first working example,realized by the control computer 3. This is the same in other workingexamples which follow, unless specified otherwise.

Over the recent years, a small-sized Peltier device formed a fewmillimeters square (e.g., approximately 1 mm-2 mm square) in size hasbeen commercialized (such as product numbers YKMG, YKMK, YKMA, YKMFmanufactured by Yamaha Corp.). Accordingly, for instance, a width of thebase sheet 41 of the glucose sensor 4 is set to, e.g., about 5 mm, inwhich case the Peltier device 9 can be formed sufficiently on thesurface of the base sheet 41 by use of the small-sized Peltier device 9as described above, and this configuration can be preferably embodied.According to this configuration, the region vicinal to the immobilizedenzyme unit 43 of the glucose sensor 4 can be directly heated or cooled.

Third Working Example

A third working example will be described with reference to FIG. 9. FIG.9 is an explanatory diagram for illustrating layout positions of thetemperature sensor 8, the Peltier device 9 and the temperature controlunit 13 according to the third working example. A different point of thelayout positions of the respective components in the third workingexample from FIG. 1 is that the housing 2 accommodates the temperaturesensor 8 in addition to the Peltier device 9. Further, the temperaturecontrol unit 13 is the same as in the example illustrated in FIG. 1. InFIG. 9, the temperature sensor 8 is disposed in, e.g., the notchedportion (the recessed portion or the cavity) of the base plate 21 in thesame way as the Peltier device 9 is.

The temperature sensor 8 in the third working example is disposed notsubcutaneously but on the skin surface, and hence the temperaturemeasured by the temperature sensor 8 is substantially coincident withthe temperature of the skin surface. The temperature of the skin surfaceis a temperature which has a correlation with or can be related to thedetected ambient temperature THs. Accordingly, in the third workingexample, the detected ambient temperature THs is estimated based on apositional relation between the position in which the immobilized enzymeunit 43 disposed subcutaneously and the position in which thetemperature sensor 8 measures the temperature (the position in which thetemperature sensor 8 is disposed) and based on the measurementtemperature measured by the temperature sensor 8.

For example, a map is generated, which is stored with the detectedambient temperature THs, the skin surface temperature measured by thetemperature sensor 8, a relational formula of a subcutaneous embeddingdepth of the immobilized enzyme unit 43 and relations therebetween,whereby the detected ambient temperature THs can be estimated bysubstituting the skin surface temperature and the embedding depththerein. Then, the temperature adjustment control explained in the firstworking example can be preferably conducted based on the thus-estimateddetected ambient temperature THs.

Moreover, in the configuration according to the third working example,the temperature sensor 8 can be disposed on the skin surface. Anadvantage of this layout is that the temperature sensor 8 does not needembedding subcutaneously, and a size of a portion, embeddedsubcutaneously, of the base sheet 41 of the glucose sensor 4 can bethereby reduced. As a result, this advantage is useful for relieving adamage to the examinee (user), which is caused when inserting theglucose sensor 4 subcutaneously and for improving facilitation of theinsertion.

To give a modified example of the third working example incidentally, inthe layout example of FIG. 10, the point that the Peltier device 9 isdisposed on the base sheet 41 of the glucose sensor 4 is different fromthe example in FIG. 9, and other points are common.

As exemplified in the first through third working examples, it isfeasible to adopt a multiple variation of layout positions of thetemperature sensor 8, the Peltier device 9 and the temperature controlunit 13 of the monitoring device 1. Further, in each layout example, thehousing 2 accommodates the temperature control unit 13, however, anyinconvenience may not be caused by disposing the temperature controlunit 13 on the base sheet 41 of the glucose sensor 4. Namely, thetemperature sensor 8, the Peltier device 9 and the temperature controlunit 13 of the monitoring device 1 can be disposed in any one of thehousing 2 accommodating the sensor control unit 12 and the glucosesensor 4.

Fourth Working Example

Next, a fourth working example will be described. FIG. 11 is a diagramillustrating an outline of a configuration of the continuous glucosemonitoring device (monitoring system) in a fourth working example. Themonitoring device 1 in the fourth working example further includes aportable display machine 16 (a result display unit) which acquires thecalculated result of the glucose concentration given by the sensorcontrol unit 12 and has a display panel 15 for displaying the calculatedresult. Namely, the monitoring device 1 can be configured by includingthe portable display machine 16. A housing 17 of the portable displaymachine 16 is fixed to the skin by the bonding film 5 in the same way asthe housing 2 is fixed. The portable display machine 16 in FIG. 11performs the wired data communications with the sensor control unit 12via a cable 18. Herein, the portable display machine 16 can be treatedas a portable display machine 16′ separated from the monitoring device1. In this case, the present invention can be also grasped by way of amonitoring system including the monitoring device 1 and the portabledisplay machine 16′. This point is the same with FIGS. 12-15 that willbe given later on.

Next, the layout positions of the temperature sensor 8, the Peltierdevice 9 and the temperature control unit 13 in the fourth workingexample will be explained. In the layout example depicted in FIG. 11,the temperature sensor 8 is disposed on the base sheet 41 of the glucosesensor 4, the temperature control unit 13 is disposed in the housing 2accommodating the sensor control unit 12, and the Peltier device 9 isdisposed in the housing 17 for the portable display machine 16. In thiscase, the Peltier device 9 is easy to be disposed at a farther distancefrom the immobilized enzyme unit 43 of the glucose sensor 4 than in thecase of disposing the Peltier device 9 in the housing 2 as illustratedin, e.g., FIG. 1. The housing 17 for the portable display machine 16 inthe fourth working example is, however, formed to have a largerprojection area on the skin surface than that of the housing 2accommodating the sensor control unit 12. It is therefore possible toavoid decreasing the efficiency when adjusting the detected ambienttemperature THs under the temperature adjustment control described aboveby increasing the number of semiconductors configuring the Peltierdevice 9 to such a degree as to get spaced away from the temperatureadjustment target immobilized enzyme unit 43.

FIGS. 12-15 illustrate the layout examples, different from FIG. 11, ofthe temperature sensor 8, the Peltier device 9 and the temperaturecontrol unit 13. The layout example depicted in FIG. 12 is that thetemperature sensor 8 is disposed in the housing 17 for the portabledisplay machine 16, the temperature control unit 13 is disposed in thehousing 2 accommodating the sensor control unit 12, and the Peltierdevice 9 is disposed on the base sheet 41 of the glucose sensor 4.Herein, in the case of disposing the temperature sensor 8 in the housing17 as illustrated therein, the temperature sensor 8 is easy to bedisposed at a still farther distance from the immobilized enzyme unit 43of the glucose sensor 4 than in the case of the disposition in thehousing 2 as in the example of, e.g., FIG. 9. The temperature of theskin surface that is measured by the temperature sensor 8 and thedetected ambient temperature THs can be, however, related to each otheras described above. Accordingly, the detected ambient temperature THscan be estimated based on the position of the immobilized enzyme unit43, the layout position of the temperature sensor 8 and the temperaturemeasured by the temperature sensor 8, and the temperature adjustmentcontrol can be preferably done based on this estimated result.

Moreover, in the layout example depicted in FIG. 13, the temperaturesensor 8 is disposed in the housing 2 accommodating the sensor controlunit 12, and the Peltier device 9 and the temperature control unit 13are disposed in the housing 17 for the portable display machine 16.Further, in the layout example illustrated in FIG. 14, the Peltierdevice 9 is disposed in the housing 2 accommodating the sensor controlunit 12, and the temperature sensor 8 and the temperature control unit13 are disposed in the housing 17 for the portable display machine 16.Moreover, in the layout example depicted in FIG. 15, all of thetemperature sensor 8, the Peltier device 9 and the temperature controlunit 13 are disposed in the housing 17 for the portable display machine16. Incidentally, as illustrated in FIGS. 13-15, a housing 16accommodates the temperature control unit 13, in which case a secondcomputer (different from the control computer 3) including a CPU, a ROMand a RAM for exhibiting the already-described functions of thetemperature control unit 13 are housed inside the housing 16, wherebythe second computer can realize the temperature control unit 13.

As exemplified in the fourth working example and the modified examplethereof, the layout positions of the temperature sensor 8, the Peltierdevice 9 and the temperature control unit 13 of the monitoring device 1can involve adopting the multiple variations. Further, the layoutexamples of the respective components are not limited to the examples inFIGS. 11-15, and any inconvenience may not be caused by disposing, e.g.,the temperature control unit 13 on the base sheet 41 of the glucosesensor 4. Then, each of the temperature sensor 8, the Peltier device 9and the temperature control unit 13 of the monitoring device 1 can bedisposed in any one of the housing 2 accommodating the sensor controlunit 12 and the glucose sensor 4 and the housing 17 provided with theportable display machine 16.

Fifth Working Example

The working examples discussed so far adopt the Peltier device 9 as thetemperature adjusting element according to the present invention on theexemplifying and not-limiting basis, however, any inconvenience may notbe caused by adopting other configurations without being limited to thePeltier device 9. As illustrated in FIG. 16, a second temperatureadjusting element 90 may be disposed as a substitute for the Peltierdevice 9 depicted in FIG. 1 etc. The second temperature adjustingelement 90 includes a micro heater serving as a heat radiation unit, aheat sink serving as a heat absorbing unit, a thermal interface materialand a heat spreader or a combination thereof.

FIG. 17 is a block diagram illustrating an outline of a configuration ofthe temperature control unit in the fifth working example. Thetemperature control unit 13 in the illustrated configuration includesthe temperature analyzing unit 13A and the power switch unit 13B butdoes not include the current switching unit 13C depicted in FIG. 6. Amicro heater 91 of the second temperature adjusting element 90 isconnected to the power switch unit 13B and adjusts a quantity of theheat radiated from the micro heater 91 by controlling the voltageapplied to the micro heater 91 from the power switch unit 13B. Asdescribed above, the second temperature adjusting element 90 has theheat sink serving as the heat absorbing unit, the thermal interfacematerial and the heat spreader (unillustrated), and, in a state ofapplying none of the drive voltage to the micro heater 91 from the powerswitch unit 13B, the heat is passively absorbed by these heat absorbingunits, thereby enabling a decrease in detected ambient temperature THsto be accelerated.

Accordingly, the micro heater 91 is operated by applying the drivevoltage to the micro heater 91 from the power switch unit 13B on theoccasion of increasing the detected ambient temperature THs, and theoperation thereof is halted by stopping the application of the voltageto the micro heater 91, whereby the detected ambient temperature THs canbe adjusted in an unrestricted manner. For example, in the processingflow of FIG. 7, in step S107, the micro heater 91 is operated byswitching ON the power switch unit 13B, thereby increasing the detectedambient temperature THs. While on the other hand, in step S108, theoperation of the micro heater 91 is halted by switching OFF the powerswitch unit 13B, thereby decreasing the detected ambient temperatureTHs. Note that it is possible to omit the step of switching OFF thepower switch unit in step S103.

Herein, the micro heater 91 itself is well known, and hence the detailedexplanation thereof is herein omitted, however, available heat emittingelements are, e.g., a laminated exothermic member described in JapanesePatent Laid-Open Publication No. S53-122942, an exothermic member for aminute chemical device described in Japanese Patent Laid-OpenPublication No. 2002-090357, surface exothermic members described inJapanese Patent Laid-Open Publication No. 2002-025757 and JapanesePatent Laid-Open Publication No. H07-014664, etc. Similarly, the heatsink may involve using heat sinks employed for an in vivo embedding typecooling device illustrated in FIG. 2 of Japanese Patent Laid-OpenPublication No. 2007-209523 and in FIGS. 1-4 of Japanese PatentLaid-Open Publication No. 2010-162189, a heat sink used for freezetherapy apparatus for the skin surface that is described in PatentApplication Publication No. 4324673, and so on. Moreover, the thermalinterface material is exemplified by white paste (thermal grease).Materials of the white paste can be exemplified by silicon oilcontaining aluminum oxide, zinc oxide or boron nitride. Further, theheat spreader can be easily composed of a metal material exhibiting ahigh thermal conductivity (such as a tungsten/molybdenum/copper-tungstenalloy, a copper-tungsten alloy, aluminum nitride ceramics, etc). Notethat the second temperature adjusting element 90 according to the fifthworking example can be applied to the layout examples depicted in FIGS.8-15.

Sixth Working Example

Next, variations different from those in the first working example withrespect to contents of the control according to the monitoring device 1will be explained. An outline of a configuration of the monitoringdevice 1 according to a sixth working example is the same as thosedepicted in FIGS. 1-6. FIG. 18 is a timing chart illustrating ameasurement cycle of the glucose concentration according to the glucosesensor 4 of the monitoring device 1 in the sixth working example. In theexample of FIG. 18, t0-t4 defines one measurement cycle. A period oft2-t3 is a “measurement period” of which the subject substance ismeasured by use of the glucose sensor 4, and a period of t0-t1 is a“measurement standby period” for which the subject substance is notmeasured by employing the glucose sensor 4.

Herein, an optimum temperature of the oxidoreductase in the immobilizedenzyme unit 43 of the glucose sensor 4 is, e.g., approximately 36°C.-37° C., and the sensor sensitivity is extremely high in thistemperature range. If the temperature of the immobilized enzyme unit 43shifts to a high temperature from the optimum temperature zone,inactivation of the enzyme occurs, which might become a factor forshortening a life-span of the sensor due to the deterioration etc. Onthe other hand, in the case of measuring the glucose concentration at alower temperature than the optimum temperature zone in order to preventthe inactivation of the enzyme in the immobilized enzyme unit 43, thereliability on the output result of the glucose sensor 4 might bedecreased.

Such being the case, under the temperature adjustment control accordingto the sixth working example, in order to establish both of restraint ofthe deterioration in the glucose sensor 4 and improvement of thereliability and the reproducibility related to the measured result ofthe glucose concentration, the detected ambient temperature THs isadjusted to the target setting temperature THtg during the measurementperiod and is adjusted to a standby target setting temperature THbduring the measurement standby period. The standby target settingtemperature THb is a target temperature given on the occasion ofadjusting the detected ambient temperature THs during the measurementstandby period and is set to a temperature lower than the target settingtemperature THtg.

At the measurement cycle, when shifting to the measurement period(t2-t3) from the measurement standby period (t0-t1), the Peltier device9 performs the heating control, thereby raising the detected ambienttemperature THs up to the target setting temperature THtg. During themeasurement period (t2-t3), the glucose sensor 4 detects the subjectsubstance once or a plurality of times, thus measuring the glucoseconcentration. Thereafter, when shifting to the measurement standbyperiod from the measurement period, the Peltier device 9 carries out thecooling control, thereby decreasing the detected ambient temperature THsdown to the standby target setting temperature THb. Note that a transitperiod (t1-t2) to the measurement period from the measurement standbyperiod is referred to as a “heating transit period”, and a transitperiod (t3-t4) to the measurement standby period from the measurementperiod is termed a “cooling transit period”.

The measurement cycle illustrated in FIG. 18 is an exemplification andcan be modified properly. Further, a length of one measurement cycle(t0-t4) and a ratio of the measurement time and the measurement standbytime may be changed corresponding to an area of the Peltier device 9(the temperature adjusting element). Note that if the Peltier device 9has a small area, the heating transit period and the cooling transitperiod can be reduced as compared with the case of having a larger area.Namely, it is feasible to decrease the ratio occupied by the heatingtransit period and the cooling transit period at the measurement cycle.As a result, a degree of freedom can be increased on the occasion ofsetting the ratio of the measurement period and the measurement standbyperiod.

FIG. 19 is a flowchart illustrating a second control routine when themonitoring device 1 in the sixth working example measures the glucoseconcentration. Steps of executing the same processes of the controlroutine illustrated in FIG. 7 are marked with the same referencenumerals and symbols, and the detailed descriptions thereof are omitted.The control program related to the second control routine is also storedin the ROM etc of the control computer 3 and is executed by theprocessor at the interval of the predetermined period of time.

In step S201, the temperature control unit 13 determines whether thereis a request for finishing the measurement standby period at the presentor not. The control computer 3 is equipped with a timer (timer device)for measuring the time, and the storage unit 14 is stored with the dataabout the measurement cycle as shown in FIG. 18. The temperature controlunit 13 refers to the time measured by the timer and the data about themeasurement cycle that is stored in the storage unit 14, and determinesthat the measurement standby period finishing request is given at apoint of time when reaching the timing corresponding to t1 in FIG. 18.Note that the timing (t1 in FIG. 18) of issuing the measurement standbyperiod finishing request may be set as timing of advancing by apredetermined period of time from the start timing (t2 in FIG. 18) ofthe measurement period.

When determining in this step that there is the measurement standbyperiod finishing request, the operation proceeds to step S101, and,whereas if not, the present routine is temporarily terminated. In stepS101, the temperature control unit 13 acquires the detected ambienttemperature THs based on the output signal of the temperature sensor 8.Subsequently, in step S102, the temperature control unit 13 compares thedetected ambient temperature THs with the target setting temperatureTHtg. The temperature control unit 13, in the case of determining thatthe absolute value of the difference between the detected ambienttemperature THs and the target setting temperature THtg falls within therange of the specified temperature difference ΔTHsh (|THs−THtg|≦ΔTHsh),decides that the detected ambient temperature THs is substantiallycoincident with the target setting temperature THtg, and the operationproceeds to step S105.

While on the other hand, if it is determined in step S102 that theabsolute value of the difference between the detected ambienttemperature THs and the target setting temperature THtg does not fallwithin the range of the specified temperature difference ΔTHsh(|THs−THtg|>ΔTHsh), the operation proceeds to step S107. In step S107,the temperature control unit 13 performs the control to switch ON thepower switch unit 13B, and controls the current switching unit 13C sothat the Peltier device 9 is supplied with the current in the firstdirection. With this control operation, the skin in the vicinity of thePeltier device 9 is heated. Upon finishing the process in step S107, theoperation loops back to step S102. In the process of step S102, ifdetermined to be negative again (S102: No), the operation proceeds tostep S107 described above, however, in this case the operation is in thestate of having already supplied the electric current in the [firstdirection] to the Peltier device 9, and therefore, after the as-is statehas been kept for a fixed period of time in step S107, the operationagain loops back to step S102. As a result, this heating processcontinues till the detected ambient temperature THs comes to the targetsetting temperature THtg.

In step S105, the glucose concentration is measured. To be specific, thesensor control unit 12 applies the voltage to between the electrodes 42of the glucose sensor 4 and calculates the glucose concentration (theblood glucose level) on the basis of the acquired response currentvalue. The glucose concentration in this step may be measured once andmay also be measured plural times.

Upon finishing the process in step S105, the operation proceeds to stepS202. In step S202, the temperature control unit 13 determines whetherthere is a request for finishing the measurement period at the presentor not. The temperature control unit 13 refers to, e.g., the timemeasured by the timer and the data about the measurement cycle that isstored in the storage unit 14, and determines that the measurementperiod finishing request is given at a point of time when reaching thetiming corresponding to t3 in FIG. 18. If determined to be negative inthis step, after standing by for the fixed period of time, thedetermination related to this step is again made repeatedly, and, ifdetermined to be affirmative, the operation proceeds to step S108. Notethat the timing (t3 in FIG. 18) when the measurement period finishingrequest is issued may also be set as timing delayed by a predeterminedperiod of time from the start timing (t2 in FIG. 18) of the measurementperiod.

In step S108, the temperature control unit 13 performs the control toswitch ON the power switch unit 13B, and controls the current switchingunit 13C so that the Peltier device 9 is supplied with the current inthe second direct ion. With this control operation, the heat of the skinin the vicinity of the Peltier device 9 is absorbed, thus cooling theskin surface. Then, the cool down temperature of the skin surface istransferred to the glucose sensor 4, thereby cooling the immobilizedenzyme unit 43. Upon finishing the process in step S108, the operationproceeds to step S203.

In step S203, the temperature control unit 13 acquires the detectedambient temperature THs on the basis of the output signal of thetemperature sensor 8. Subsequently, in step S203, the temperaturecontrol unit 13 compares the detected ambient temperature THs with thestandby target setting temperature THb, and determines whether or not anabsolute value of a difference therebetween falls within a range of asecond specified temperature difference ΔTHsh2. As described above, thestandby target setting temperature THb is the target temperature givenwhen adjusting the detected ambient temperature THs during themeasurement standby period and is set to the temperature lower than thetarget setting temperature THtg.

If determined to be affirmative in step S203 (|THs−THg|≦ΔTHsh2), thedetected ambient temperature THs gets coincident with the standby targetsetting temperature THb or a temperature that is sufficientlyapproximate to the standby target setting temperature THb. Whereas ifdetermined to be negative in step S203 (|THs−THg|>ΔTHsh2), the operationloops back to the process in step S108. When the operation thus loopsback to the process in step S108, the operation is in the state ofhaving already supplied the electric current in the second direction tothe Peltier device 9, and therefore, after the as-is state has been keptfor a fixed period of time in step S108, the operation again proceeds tostep S203. As a result, this cooling process of the Peltier device 9continues till the detected ambient temperature THs descends down to thestandby target setting temperature THb. If determined to be affirmativein step S203, the detected ambient temperature THs is determined todecrease down to the standby target setting temperature THb.Subsequently, the operation proceeds to step S103, and, after the powerswitch unit 13B has been switched OFF, the present routine istemporarily finished.

As described above, under the temperature adjustment control accordingto the sixth working example, the detected ambient temperature THs isadjusted to be coincident with the target setting temperature THtgduring the measurement period of each measurement cycle and ismaintained to the standby target setting temperature THb set on thelower temperature side than the target setting temperature THtg duringthe measurement standby period. Therefore, the temperature ambient tothe immobilized enzyme unit 43 of the glucose sensor 4 is kept in theoptimum temperature zone of the enzyme activity only during themeasurement period of each measurement cycle and can be maintained inthe temperature zone on the lower temperature side than the optimumtemperature zone during other periods. Accordingly, it is possible toestablish both of the restraint of the deterioration in the glucosesensor 4 and the improvement of the reliability and the reproducibilityof the measured result.

Note that the detected ambient temperature THs is decreased positivelydown to the standby target setting temperature THb during themeasurement standby period in the control example given above, however,for instance, the setting during the measurement standby period may beended up with simply keeping the Peltier device 9 in a non-operatingstate. In this case, the Peltier device 9 does not perform the coolingcontrol, which therefore leads to saving the drive power of the Peltierdevice 9. Further, the detected ambient temperature THs decreases duringthe measurement standby period as the factors may be, and it thereforefollows that the temperature of the immobilized enzyme unit 43 does notshift on the higher temperature side than the optimum temperature zone.

Seventh Working Example

In a seventh working example, the monitoring device 1 implements settingvalue adjustment control for adjusting the target setting temperatureTHtg under the temperature adjustment control. This setting valueadjustment control is conducted based on the measured result of theglucose concentration acquired by the monitoring device 1 and a secondmonitoring device 50 that will be described later on. A hardwareconfiguration of the monitoring device 1 according to the seventhworking example is the same as in the first working example (see FIGS.1-6), and the detailed explanation thereof is omitted.

FIG. 20 is a diagram of an outline of a configuration of the secondmonitoring device 50. The second monitoring device 50 is an SMBG (SelfMonitoring of Blood Glucose) device capable of measuring the glucoseconcentration (blood glucose level) in the body fluid (blood,interstitial liquid, etc.) captured in vitro, and measures the bloodglucose level by use of the blood bled in vitro such as a drop of fingerblood. The blood sampled in vitro from the examinee is referred to as asecond sample as the case may be.

The second monitoring device 50 measures the glucose concentration ofthe second sample by an electrochemical technique using a biosensor 60.The second monitoring device 50 includes a housing 61, a display panel62, an operation button 63 and a sensor insertion port 68. Further, thesecond monitoring device 50 has, though its illustration is omitted, acircuit board mounted with electronic components such as a CPU, a RAMand a ROM required for predetermined operations (such as applying thevoltage and performing the communications with the outside) of thesecond monitoring device 50.

As shown in FIG. 20, the housing 61 is provided with the display panel62 and the plurality of operation buttons 63. The plurality of operationbuttons 63 is used for executing operations such as setting a variety ofmeasurement conditions and starting/finishing the measurement. Theplurality of operation buttons 63 may also be provided on a contact typetouch panel. The display panel 62 displays the measured result and anerror, and also displays operation procedures and operation states whensetting. The display panel 62 is exemplified by a liquid crystal displaydevice, a plasma display panel, a Cathode Ray Tube (CRT) or anelectroluminescence panel. The biosensor 60 is a known sensor in which asample layer containing, e.g., an electron transfer substance and theoxidoreductase is formed on the base plate.

Respective functions provided in the second monitoring device 50 will beexplained. FIG. 21 is a function block diagram of the second monitoringdevice 50. The second monitoring device 50 includes a communication unit80, a power source unit 81, a control unit 82, a measuring unit 83 and astorage unit 84. The communication unit 80 performs the datacommunications between the monitoring device 1 and the second monitoringdevice 50. The data communications can involve utilizing, e.g., thewireless communication means. Further, the wired data communications mayalso be conducted by establishing a connection between the monitoringdevice 1 and the second monitoring device 50 via a cable of a USB(Universal Serial Bus) etc. The power source unit 81 supplies theelectric power for driving the second monitoring device 50. For example,the function as the power source unit 81 may be actualized by use of abutton battery having a power voltage on the order or 1V-3V. The controlunit 82 controls the communications with, e.g., the monitoring device 1.

The measuring unit 83 measures the glucose concentration (blood glucoselevel) of the glucose contained in the blood (the second sample) broughtinto contact with the sensor unit (sample layer) of the biosensor 60.Then, the storage unit 84 gets stored with the glucose concentrationmeasured by the measuring unit 83 in the way of being associated withthe measurement time information thereof. The measured result of theglucose concentration in the blood, which is measured by thethus-configured second monitoring device 50, is transmitted to thecommunication unit 11 in the monitoring device 1 from the communicationunit 80 of the second monitoring device 50.

The continuous measurement of the glucose concentration by use of themonitoring device 1 continues over a comparatively long period of time(e.g., approximately one week) in many cases, and hence the sensitivityof the glucose sensor 4 is lowered as the case may be due to thedeterioration as the glucose oxidoreductase in the immobilized enzymeunit 43 is affected by repeatedly applying the voltage or due to gradualadhesion/deposition of the cell tissues to and on the periphery of theimmobilized enzyme unit 43. Further, if the sensitivity of the glucosesensor 4 declines stepwise as the continuous measurement periodelongates, an error might occur between the measurement value of theglucose concentration and a true glucose concentration.

The seventh working example involves periodically performing thefollowing setting value adjustment control when the monitoring device 1continuously measures the glucose concentration. FIG. 22 is a flowchartshowing a setting value adjustment control routine according to theseventh working example. A program related to this control routine isstored in the ROM of the control computer 3 in the monitoring device 1and is executed as triggered by receiving a setting value adjustmentcontrol start signal from the second monitoring device 50.

Upon executing this control routine, in step S301, the communicationunit 11 receives, from the communication unit 80 of the secondmonitoring device 50, the measurement time information and themeasurement value (which will hereinafter be termed an “SMBG measurementvalue Vsmbg” (corresponding to second numerical value information)) whenthe second monitoring device 50 measures the glucose concentration ofthe second sample. Then, in step S302, the storage unit 14 in themonitoring device 1 is stored with the SMBG measurement value Vsmbgreceived by the communication unit 11 in the way of being as with themeasurement time information thereof.

Moreover, the storage unit 14 is stored with the glucose concentrationmeasurement values (which will hereinafter be termed “CGM measurementvalues Vcgm” (corresponding to first numerical value information))measured by the sensor control unit 12 up to the present time afterstarting the continuous measurement of the glucose concentration andwith the measurement time information in the way of being associatedwith each other. When the update data of the SMBG measurement valueVsmbg is added to the storage unit 14, the temperature control unit 13extracts, in step S303, the measurement time information associated withthe updated SMBG measurement value Vsmbg and the CGM measurement valueVcgm measured at the nearest point of time. As a result, the temperaturecontrol unit 13 can acquire the CGM measurement value Vcgm and the SMBGmeasurement value Vsmbg which are measured substantially at the samepoint of time. Subsequently, the temperature control unit 13 calculatesan absolute value between the SMBG measurement value Vsmbg and the CGMmeasurement value Vcgm (which will hereinafter be referred to as a“measurement absolute error ΔVa”).

The temperature control unit 13 determines whether the measurementabsolute error ΔVa exceeds a first reference value ΔVb1 or not. If themeasurement absolute error ΔVa is determined equal to or smaller thanthe first reference value ΔVb1 (ΔVa≦ΔVb1), it is concluded that theglucose sensor 4 has the adequate sensitivity and the glucoseconcentration contains almost no measurement error. Such being the case,when determining in this step that the measurement absolute error ΔVa isequal to or smaller than the first reference value ΔVb1 (ΔVa ΔVb1), thepresent routine is temporarily finished. In this case, this is becausethe determination is that the sensitivity of the glucose sensor 4 doesnot need adjusting specially. Whereas if it is determined that themeasurement absolute error ΔVa exceeds the first reference value ΔVb1(ΔVa>ΔVb1), the operation proceeds to step S304.

In step S304, the temperature control unit 13 changes the setting valueof the target setting temperature THtg. Herein, a change width of thetarget setting temperature THtg is adjusted corresponding to a magnitudeof the measurement absolute error ΔVa. A difference of the measurementvalue, which is acquired by subtracting the CGM measurement value Vcgmfrom the SMBG measurement value Vsmbg, is expressed by a “measurementerror ΔVr”. In this routine, the temperature setting change value ΔTHtgobtained by multiplying the measurement error ΔVr by a constant C1(where C1>0) is added to the present target setting temperature THtg,thus calculating a post-modifying target setting temperature (which willhereinafter be referred to as a “target modified temperature THtgm”)(THtgm=THtg+ΔTHtg, ΔTHtg=C1×ΔVr). Note that the calculation formula isan exemplification, and the calculation is not limited to this formula.When terminating the process in this step, the present routine istemporarily finished.

The SMBG measurement value Vsmbg is obtained by measuring the glucoseconcentration in a way that uses, as the sample, the blood sampled invitro from the examinee. Therefore, the reliability of the measuredresult thereof is higher than the CGM measurement value Vcgm measured byemploying the subcutaneous indwelling type glucose sensor 4. Hence,herein the SMBG measurement value Vsmbg is deemed to be the true glucoseconcentration.

If the glucose sensor 4 has a low sensitivity, the CGM measurement valueVcgm is lower than the SMBG measurement value Vsmbg in many cases. Inthis instance, the measurement error ΔVr takes the positive value,whereby the temperature setting change value ΔTHtg takes the positivevalue. As a result, the target setting temperature THtg is corrected onthe high-temperature side to thereby accelerate the enzyme activity inthe immobilized enzyme unit 43, and it is possible to increase thesensor sensitivity of the glucose sensor 4. While on the other hand, ifthe sensitivity of the glucose sensor 4 excessively rises, an assumptionis that the CGM measurement value Vcgm is higher than the SMBGmeasurement value Vsmbg. In this case, the measurement error ΔVr takesthe negative value, whereby the temperature setting change value ΔTHtgalso takes the negative value. As a result, the target settingtemperature THtg is corrected on the low-temperature side to therebydecelerate the enzyme activity in the immobilized enzyme unit 43, and itis possible to decrease the sensor sensitivity of the glucose sensor 4.As discussed above, the target setting temperature THtg is adjustedcorresponding to the magnitude of the measurement error ΔVr under thiscontrol, thereby enabling the monitoring device 1 to enhance themeasurement accuracy of the glucose concentration. Moreover, if the CGMmeasurement value Vcgm is higher than the SMBG measurement value Vsmbg,the target setting temperature THtg is modified on the low-temperatureside, and it is therefore feasible to further surely avoid theoccurrence of the deterioration due to such a point that the temperatureof the immobilized enzyme unit 43 in the glucose sensor 4 gets higherthan the optimum temperature zone of the enzyme.

Under the setting value adjustment control according to the seventhworking example, the setting value of the target setting temperatureTHtg is changed corresponding to the magnitude of the measurement errorΔVr, and hence, even when the deterioration etc is caused as derivedfrom the continuous use of the glucose sensor 4, the sensor sensitivityin the glucose sensor 4 can be properly maintained, with the result thatthe reliabilities of the measurement accuracy and the measurement resultcan be enhanced.

Modified Example

Next, a modified example of the setting value adjustment control in theseventh working example will be explained. The storage unit 14 is storedwith calibration curve data representing an associative relation betweenthe response current value and the glucose concentration each given fromthe glucose sensor 4 in the form of a mathematical expression and anassociative table.

Further, plural sets of calibration curve data are preparedcorresponding to the sensor sensitivities of the glucose sensor 4 andare stored in the storage unit 14. In this case, if the measurementabsolute error ΔVa exceeds the first reference value ΔVb1, the sensorcontrol unit 12 selects another set of calibration curve datacorresponding to the measurement error ΔVr, whereby the glucose sensor 4may improve the measurement accuracy of the glucose concentration. Insuch a case also, the calibration curve data count is finite. Therefore,as under the setting value adjustment control described above, theadjustment of the target setting temperature THtg under the temperatureadjustment control with reference to the SMBG measurement value Vsmbgtransmitted from the side of the second monitoring device 50 is highlyeffective in minutely adjusting the sensor sensitivity. It is becausethe setting value adjustment control described above enables therespective sets of calibration curve data to be effectivelyinterpolated.

Moreover, in the flowchart shown in FIG. 22, only one threshold valuefor the measurement absolute error ΔVa is provided, however, theplurality of threshold values may also be provided.

FIG. 23 is a flowchart showing a second setting value adjustment controlroutine according to the seventh working example. The program related tothis control routine is stored in the ROM of the control computer 3 inthe monitoring device 1 and is executed as triggered by receiving thesetting value adjustment control start signal from the second monitoringdevice 50. The steps of executing the same processes as those in theprocessing flow illustrated in FIG. 22 are marked with the samereference numerals and symbols, and the in-depth descriptions thereofare omitted.

In step S303, when determining that the measurement absolute error ΔVaexceeds the first reference value ΔVb1 (ΔVa>ΔVb1), the operationproceeds to step S305. In step S305, the temperature control unit 13determines whether the measurement absolute error ΔVa exceeds a secondreference value ΔVb2 or not. The second reference value ΔVb2 is athreshold value for determining whether the calibration curve data usedfor calculating the glucose concentration needs changing or not, and isset to a value larger than the first reference value ΔVb1. Whendetermining that the measurement absolute error ΔVa is equal to orsmaller than the second reference value ΔVb2 (ΔVb1<ΔVa≦ΔVb2), it isconcluded that the calibration curve data used for calculating theglucose concentration does not need changing. In this case, theoperation proceeds to step S304, in which the setting value of thetarget setting temperature THtg is changed corresponding to themagnitude of the measurement absolute error ΔVa.

While on the other hand, when determining the measurement absolute errorΔVa exceeds the second reference value ΔVb2 (ΔVa>ΔVb2), the operationproceeds to step S306. In step S306, the sensor control unit 12 changesthe calibration curve data used for calculating the glucoseconcentration. The sensor control unit 12 reselects the calibrationcurve data to enhance the sensor sensitivity if the measurement errorΔVr takes the positive value and reselects the calibration curve data tolower the sensor sensitivity if the measurement error ΔVr takes thenegative value. Then, upon finishing the process in this step, thepresent routine is temporarily terminated. Incidentally, in step S306,along with the change in setting (selection) of the calibration curvedata, the setting value of the target setting temperature THtg may bechanged in the same way as in step S304. With this operation, the sensorsensitivity of the glucose sensor 4 can be corrected more minutely.

According to the control example shown in FIG. 23, when the measurementabsolute error ΔVa is comparatively small, the sensitivity of theglucose sensor 4 can be adjusted without reselecting the calibrationcurve data. Further, even if the deterioration of the glucose sensor 4progresses due to the elongation of the continuous measurement period ofthe blood glucose level, it is feasible to expand the adjustment widthof the sensor sensitivity of the glucose sensor 4 by reselecting thecalibration curve data used for measuring the glucose concentration.Moreover, the target setting temperature THtg is corrected together asthe necessity may arise, whereby it is possible to establish both ofensuring the adjustment width of the sensor sensitivity of the glucosesensor 4 and making the more minute adjustment. In the seventh workingexample, the first reference value ΔVb1 corresponds to a first thresholdvalue according to the present invention.

Eighth Working Example

The seventh working example has discussed the control example formodifying the setting value of the target setting temperature THtgduring the measurement period of each measurement cycle, however, aneighth working example will discuss a control example for adjusting asetting value of the standby target setting temperature THb during themeasurement standby period. Hardware configurations of the monitoringdevice 1 and the second monitoring device 50 according to the eighthworking example are the same as the hardware configurations in the sixthworking example. FIG. 24 is a flowchart showing a setting valueadjustment control routine according to the eighth working example. Theprogram related to this control routine is stored in the ROM of thecontrol computer 3 in the monitoring device 1 and is executed astriggered by receiving the setting value adjustment control start signalfrom the second monitoring device 50. The steps of executing the sameprocesses as those in the processing flow illustrated in FIGS. 22 and 23are marked with the same reference numerals and symbols, and thein-depth descriptions thereof are omitted.

Upon executing the present control routine, in step S301, thecommunication unit 11 receives, from the communication unit 80 of thesecond monitoring device 50, the SMBG measurement value Vsmbg measuredfrom the second sample by the second monitoring device 50 and themeasurement time information associated therewith. In step S302, thestorage unit 14 is stored with the SMBG measurement value Vsmbg receivedby the communication unit 11 in the way of being associated with themeasurement time information. When update data of the SMBG measurementvalue Vsmbg is added to the storage unit 14, the temperature controlunit 13 extracts, in subsequent step S401, data (information) of the CGMmeasurement value Vcgm measured at the time nearest to the measurementtime associated with the SMBG measurement value Vsmbg. This schemeenables the temperature control unit 13 to acquire the CGM measurementvalue Vcgm and the SMBG measurement value Vsmbg that are measuredsubstantially at the same point of time (approximately at the same pointof time).

The temperature control unit 13 calculates the measurement error ΔVr bysubtracting the CGM measurement value Vcgm from the acquired SMBGmeasurement value Vsmbg. Then, the temperature control unit 13determines whether the measurement error ΔVr exceeds a third referencevalue ΔVb3 or not. The third reference value ΔVb3 is a threshold valuefor determining whether or not the sensor sensitivity declines due tothe adhesion/deposition of the subcutaneous tissues and thedeterioration of the immobilized enzyme unit 43. Herein, whendetermining that the measurement error ΔVr is equal to or smaller thanthe third reference value ΔVb3 (ΔVr≦ΔVb3), it is concluded that thesensor sensitivity has almost no decline due to the deterioration etc ofthe immobilized enzyme unit 43 of the glucose sensor 4, and the presentroutine is temporarily terminated. While on the other hand, whendetermining that the measurement error ΔVr exceeds the third referencevalue ΔVb3 ((ΔVr>ΔVb3), it is concluded that the sensor sensitivitydeclines due to the deterioration etc of the immobilized enzyme unit 43,and in this case the operation proceeds to step S402.

In step S402, the temperature control unit 13 changes the setting valueof the standby target setting temperature THb during the measurementstandby period of each measurement cycle. A change width of the standbytarget setting temperature THb is adjusted corresponding to themagnitude of the measurement error ΔVr. In the present routine, thetemperature setting change value ΔTHb acquired by multiplying themeasurement error ΔVr by a constant C2 (where C2>0) is set as apost-modifying standby target setting temperature (which willhereinafter be termed a “standby target modified temperature THbm”)through the subtraction from the present standby target settingtemperature THb (THbm=THbg+ΔTHb, ΔTHb=C2×ΔVr). Herein, if the SMBGmeasurement value Vsmbg is larger than the CGM measurement value Vcgm,the temperature setting change value ΔTHb takes the positive value, andhence the standby target modified temperature THbm is changed on thelower temperature side than the present standby target settingtemperature THb. Upon finishing the process in this step, the presentroutine is temporarily terminated. Note that the calculation formula isan exemplification, and the calculation is not limited to this formula.

Thus, under the setting value adjustment control according to the eighthworking example, the setting value of the standby target settingtemperature THb during the measurement standby period is adjustedcorresponding to the magnitude of the measurement error ΔVr, andtherefore it is feasible to hinder the deterioration of the glucosesensor 4 and to delay the progress thereof. Accordingly, even when thecontinuous measurement period of the glucose concentration elongates,the measurement accuracy can be restrained from decreasing. In theeighth working example, the third reference value ΔVb3 corresponds to asecond threshold value according to the present invention.

Modified Example

Next, a modified example of the setting value adjustment control in theeighth working example will be described. FIG. 25 is a flowchart showinga second setting value adjustment control routine according to theeighth working example. The program related to this control routine isstored in the ROM of the control computer 3 in the monitoring device 1and is executed as triggered by receiving the setting value adjustmentcontrol start signal from the second monitoring device 50. In theflowchart shown in FIG. 24, only one threshold value is provided for themeasurement error ΔVr, however, the plurality of threshold values isprovided herein. In FIG. 25, the steps of executing the same processesas those in the processing flow illustrated in FIGS. 22 through 24 aremarked with the same reference numerals and symbols, and the in-depthdescriptions thereof are omitted.

In the present control routine, in step S401, when determining that themeasurement error ΔVr exceeds the third reference value ΔVb3 (ΔVr>ΔVb3),the operation proceeds to step S403. In step S403, the temperaturecontrol unit 13 determines whether the measurement error ΔVr exceeds afourth reference value ΔVb4 or not. When determining that themeasurement error ΔVr is equal to or smaller than the fourth referencevalue ΔVb4 (ΔVb3<ΔVr≦ΔVb4), the operation proceeds to step S404, and,whereas if not (ΔVr>ΔVb4), the operation proceeds to step S405.Incidentally, when determining in step S401 that the measurement errorΔVr is equal to or smaller than the third reference value ΔVb3(ΔVr≦ΔVb3), the present routine is temporarily terminated.

In step S404, the temperature control unit 13 calculates the standbytarget modified temperature THbm in a way that subtracts, from thepresent standby target setting temperature THb, the temperature settingchange value ΔTHb obtained by multiplying the measurement error ΔVr bythe constant C2 (where C2>0) (THbm==THb−ΔTHb, ΔTHb=C2×ΔVr). Note thatthe calculation formula is an exemplification, and the calculation isnot limited to this formula. Upon finishing the process in step S404,the operation proceeds to step S406. A content of the process in stepS406 will be described later on, and hence, at first, a content of theprocess in step S405 is herein explained.

In step S405, the temperature control unit 13 determines whether themeasurement error ΔVr exceeds a fifth reference value ΔVb5 or not. Thefifth reference value ΔVb5 is a threshold value set to a value largerthan the fourth reference value ΔVb4, and, if the measurement error ΔVrexceeds the fifth reference value ΔVb5, it is concluded that the use ofthe glucose sensor 4 should be interrupted because of an outstandingprogress of the deterioration of the immobilized enzyme unit 43. In stepS405, when determining that the measurement error ΔVr exceeds the fifthreference value ΔVb5 (ΔVr>ΔVb5), the operation proceeds to step S407. Instep S407, the temperature control unit 13 outputs, to the sensorcontrol unit 12, an instruction (instruction signal) having a content ofstopping the measurement of the glucose concentration by the glucosesensor 4, thus interrupting the measurement of the glucose concentration(step S407). In this case, the monitoring device 1 informs the user thatthe continuous measurement of the glucose concentration is interruptedand informs the user of information having a content of prompting theuser to replace the glucose sensor 4 with a new glucose sensor 4 bydisplaying these items of information on the display panel 15 of theportable display machine 16. Alternatively, the monitoring device 1 maygive an alarm having a content of prompting the user to replace theglucose sensor 4 with a new glucose sensor 4 in order to call the user'sattention without forcibly interrupting the continuous measurement ofthe glucose concentration. Upon finishing the process in this step, thepresent routine is temporarily terminated.

Further, in step S405, when determining that the measurement error ΔVris equal to or smaller than the fifth reference value ΔVb5(ΔVb4<ΔVr≦ΔVb5), the operation proceeds to step S408. In step S408, thetemperature control unit 13 calculates the standby target modifiedtemperature THbm in a way that subtracts, from the present standbytarget setting temperature THb, a temperature setting change value ΔTHb′obtained by multiplying the measurement error ΔVr by a constant C3(where C3>C2) (THbm==THb−ΔTHb′, ΔTHb′=C3×ΔVr). Note that the calculationformula is an exemplification, and the calculation is not limited tothis formula.

The fifth reference value ΔVb5 is a threshold value set to a valuelarger than the fourth reference value ΔVb4, and hence, if determined tobe affirmative in step S403, i.e., when determining that the measurementerror ΔVr exceeds the fourth reference value ΔVb4, it is concluded thatthe deterioration of the glucose sensor 4 shows more of the progress ofthe deterioration of the glucose sensor 4 than in the case of making thenegative determination. By contrast, the constant C3 defined as areduction coefficient of the standby target setting temperature THb isset larger than the constant C2, so that the temperature setting changevalue ΔTHb′ calculated in step S408 is larger than the temperaturesetting change value ΔTHb calculated in step S404. As a result, thedecrease width of the standby target setting temperature THb can be setlarger as the glucose sensor 4 comes to have a higher degree of itsdeterioration, thereby enabling the progress of the deterioration of theglucose sensor 4 to be preferably retarded.

Upon finishing the process in step S408, the operation proceeds to stepS406. The temperature control unit 13 determines whether the standbytarget modified temperature THbm calculated in step S404 or S408 islower than a predetermined allowable minimum temperature THbb or not.Herein, the allowable minimum temperature THbb is the minimumtemperature of the detected ambient temperature THs, at which theexaminee feels neither a sense of discomfort nor displeasure. Theallowable minimum temperature THbb can be also preset and can be setvariably by accepting a manual input from the user. In step S406, ifdetermined to be affirmative (THbm<THbb), the operation proceeds to stepS407. Whereas if determined to be negative (THbm≧THbb), the operationproceeds to step S409.

Note that the determining process in step S406, i.e., the process ofdetermining whether or not the standby target modified temperature THbmis lower than the allowable minimum temperature THbb, is notindispensable but may be omitted. In this case, it is preferable thatthe operation proceeds directly to step S409. In step S409, thetemperature control unit 13 changes the setting value of the standbytarget setting temperature THb to the standby target modifiedtemperature THbm from the present setting value. This standby targetmodified temperature THbm is a value calculated in step S404 or S408.Upon finishing the process in this step, the present routine istemporarily terminated.

As discussed above, under the control according to this modifiedexample, the plurality of threshold values is provided for themagnitudes of the measurement errors ΔVr, and it is therefore feasibleto properly take, corresponding to the degree of deterioration, themeasure for preventing the deterioration of the glucose sensor 4 fromprogressing. Furthermore, on the occasion of setting the standby targetmodified temperature THbm, the allowable minimum temperature THbb is setso that the detected ambient temperature THs does not become excessivelylow, and hence the examinee feels neither the sense of discomfort northe displeasure.

Moreover, under the setting value adjustment control according to theeighth working example, the case of adjusting the standby target settingtemperature THb during the measurement standby period of eachmeasurement cycle has been discussed, however, the control according tothe sixth working example described above, i.e., the adjustment of thetarget setting temperature THtg during the measurement period may becarried out together.

Ninth Working Example

A ninth working example involves, on the occasion of the glucosecontinuous measurement, adjusting the detected ambient temperature THsduring both of the measurement period and the measurement standby periodof the measurement cycle on the basis of a difference between the CGMmeasurement values Vcgm acquired at first timing Tm1 and second timingTm2 before an elapse of the predetermined first period ΔTm1(corresponding to a predetermined period) from the first timing Tm1. Thehardware configurations of the monitoring device 1 and the secondmonitoring device 50 according to the ninth working example are the sameas those in the seventh working example.

FIG. 26 is a flowchart showing a setting value adjustment controlroutine according to the ninth working example. The program related tothis control routine is stored in the ROM of the control computer 3 inthe monitoring device 1. The steps of executing the same processes asthose in the processing flow illustrated in FIGS. 22 through 25 aremarked with the same reference numerals and symbols, and the in-depthdescriptions thereof are omitted.

In step S501, the temperature control unit 13 accesses the storage unit14 and thus acquires the updated SMBG measurement value Vsmbg via thecommunication unit 11. Then, the temperature control unit 13 acquiresthe SMBG measurement value Vsmbg (which will hereinafter be termed a“second SMBG measurement value Vsmbg2”) stored in the storage unit 14 atthe nearest point of time which traces back to at least the first periodΔTm1 or longer from the point of time when measuring the acquiredupdated SMBG measurement value Vsmbg (which will hereinafter be termed a“first SMBG measurement value Vsmbg1”).

Subsequently, in step S502, the temperature control unit 13 determineswhether or not an absolute value of a difference (which will hereinafterbe termed a “second measurement absolute error ΔVa2”) between the firstSMBG measurement value Vsmbg1 and the second SMBG measurement valueVsmbg2 is equal to or smaller than a sixth reference value ΔVb6 (a thirdthreshold value). If the second measurement absolute error ΔVa2 is equalto or smaller than the sixth reference value ΔVb6 (ΔVa2≦ΔVb6), theoperation proceeds to step S503, and, whereas if not (ΔVa2>ΔVb6), thepresent routine is temporarily terminated.

The first period ΔTm1 is set to a period that is relatively long foreach measurement cycle of the continuous measurement in the monitoringdevice 1, e.g., set to a few or several hours through about one day butmay be properly changed without being limited to this time range. Thesixth reference value ΔVb6 is a threshold value for determining whetheror not the glucose concentration of the examinee fluctuates at a smalllevel before and after the elapse of the thus-set first period ΔTm1,and, if the second measurement absolute error ΔVa2 falls within a rangeof this sixth reference value ΔVb6 or smaller, the fluctuation inglucose concentration is determined to be small.

In step S503, the temperature control unit 13 acquires the CGMmeasurement value Vcgm (which will hereinafter be termed a “first CGMmeasurement value Vcgm1”) measured at the timing nearest to themeasurement time of the first SMBG measurement value Vsmbg1 and the CGMmeasurement value Vcgm (which will hereinafter be termed a “second CGMmeasurement value Vcgm2”) measured at the timing nearest to themeasurement time of the second SMBG measurement value Vsmbg2. Herein,when setting the measurement time of the first CGM measurement valueVcgm1 as the first timing Tm1 and the measurement time of the second CGMmeasurement value Vcgm2 as the second timing Tm2, the first timing Tm1is the timing after an elapse of approximately the first period ΔTm1from the second timing Tm2. A difference between the elapse period fromthe second timing Tm2 to the first timing Tm1 and the first period ΔTm1is, more or less, said to be a period that is short enough to beignorable as compared with the first period ΔTm1.

In step S504, the temperature control unit 13 calculates an absolutevalue (which will hereinafter be referred to as a “third measurementabsolute error ΔVa3”) of a difference between the first CGM measurementvalue Vcgm1 and the second CGM measurement value Vcgm2. Then, thetemperature control unit 13 determines whether or not the thirdmeasurement absolute error ΔVa3 exceeds a seventh reference value ΔVb7(a fourth threshold value). Herein, the seventh reference value ΔVb7 isa threshold value for determining whether the sensitivity of the glucosesensor 4 is proper or not. If the third measurement absolute error ΔVa3is equal to or smaller than the seventh reference value ΔVb7, it isconcluded that the sensitivity of the glucose sensor 4 is proper and theglucose concentration contains almost no measurement error. In thisstep, when determining that the third measurement absolute error ΔVa3 isequal to or smaller than the seventh reference value ΔVb7 (ΔVa3≦ΔVb7),it is concluded that the sensitivity of the glucose sensor 4 does notneed adjusting specially, and the operation proceeds to step S505.Whereas if the third measurement absolute error ΔVa3 is determined toexceed the seventh reference value ΔVb7 (ΔVa3>ΔVb7), the operationproceeds to step S506.

In step S506, the temperature control unit 13 changes the setting valueof the target setting temperature THtg related to the measurement periodof the measurement cycle. Herein, a difference between the measurementvalues, which is obtained by subtracting the second CGM measurementvalue Vcgm2 from the first CGM measurement value Vcgm1, is referred toas a “second measurement error ΔVr2”. In this step S506, the changewidth of the target setting temperature THtg is adjusted correspondingto a magnitude of the second measurement error ΔVr2. To be specific, thetarget modified temperature THtgm is calculated by adding thetemperature setting change value ΔTHtg obtained by multiplying thesecond measurement error ΔVr2 by a constant C4 (where C4>0) to thepresent target setting temperature THtg (THtgm=THtg+ΔTHtg,ΔTHtg=C4×ΔVr2). Note that the calculation formula is an exemplification,and the calculation is not limited to this formula.

Herein, if the second measurement error ΔVr2 takes the positive value,the temperature setting change value ΔTHtg is modified on thehigh-temperature side, and hence the sensor sensitivity of the glucosesensor 4 can be enhanced. While on the other hand, if the secondmeasurement error ΔVr2 takes the negative value, the temperature settingchange value ΔTHtg is modified on the low-temperature side, andtherefore the sensor sensitivity of the glucose sensor 4 can be lowered.As described above, in the present control example, the change width ofthe target setting temperature THtg is adjusted corresponding to themagnitude of the second measurement error ΔVr2, thereby enabling themonitoring device 1 to increase the measurement accuracy of the glucoseconcentration. Further, if the second CGM measurement value Vcgm2 ishigher than the first CGM measurement value Vcgm1, the target settingtemperature THtg is modified on the low-temperature side, and it istherefore possible to more surely avoid the occurrence of thedeterioration caused by such a point that the temperature of theimmobilized enzyme unit 43 of the glucose sensor 4 becomes higher thanthe optimum temperature zone of the enzyme. Upon finishing the processin this step, the present routine is temporarily terminated.

On the other hand, in step S505, the temperature control unit 13accesses the aforementioned timer (the illustration is omitted) and thusacquires the second period ΔTm2 defined as an elapse period reaching thefirst timing Tm1 since the continuous measurement of the glucoseconcentration has been started.

Subsequently, in step S507, the temperature control unit 13 determineswhether or not the second period ΔTm2 exceeds the predeterminedreference period ΔTmb. The reference period ΔTmb is a period serving asa threshold value from which to determine that the immobilized enzymeunit 43 of the glucose sensor 4 does not start getting deteriorated whenthe continuous usage period of the glucose sensor 4 is within thisreference period ΔTmb. When determining that the second period ΔTm2 iswithin the reference period ΔTmb (ΔTm2≦ΔTmb), the present routine istemporarily terminated in status quo. While on the other hand, whendetermining that the second period ΔTm2 exceeds the reference periodΔTmb (ΔTm2>ΔTmb), the operation proceeds to step S508.

In step S508, the temperature control unit 13 changes the setting valueof the standby target setting temperature THb during the measurementstandby period of each measurement cycle. The change width of thestandby target setting temperature THb is adjusted corresponding to amagnitude of the third measurement absolute error ΔVa3. Herein, astandby target modified temperature THbm is calculated by subtracting,from the present target setting temperature THtg, the temperaturesetting change value ΔTHb obtained by the third measurement absoluteerror ΔVa3 by a constant C5 (where C5>0) (THbm=THb−ΔTHb, ΔTHb=C5×ΔVa3).Note that the calculation formula is an exemplification, and thecalculation is not limited to this formula.

In this step, the decrease width of the standby target settingtemperature THb from the present setting value is set larger with agreater gap quantity between the second CGM measurement value Vcgm2 andthe first CGM measurement value Vcgm1, which are obtained by themonitoring device 1 at different two points of timing before and afterthe first period ΔTm1. Then, when the second period ΔTm2 reaching thefirst timing Tm1 since the continuous measurement of the glucoseconcentration has been started exceeds the reference period ΔTmb, thesetting value of the standby target setting temperature THb is changedon the low-temperature side, thereby enabling the progress of thedeterioration of the glucose sensor 4 to be preferably hindered. Uponfinishing the process in this step, the present routine is temporarilyterminated.

In the control routine illustrated in FIG. 26, the setting values ofboth of the target setting temperature THtg and the standby targetsetting temperature THb are changed based on the gap quantity betweenthe first CGM measurement value Vcgm1 and the second CGM measurementvalue Vcgm2, however, for instance, an available scheme is that thesetting value of any one of the temperatures is changed.

Moreover, a modified example of the control routine shown in FIG. 26 isthat the temperature control unit 13, e.g., in step S506, determinesbefore changing the setting value of the target setting temperature THtgwhether or not the first CGM measurement value Vcgm1 is smaller than thesecond CGM measurement value Vcgm2, and, if determined to be affirmative(Vcgm1<Vcgm2), can modify the setting value of the target settingtemperature THtg as described above. Then, when determining that thefirst CGM measurement value Vcgm1 is equal to or larger than the secondCGM measurement value Vcgm2 (Vcgm1 Vcgm2), the present routine may befinished in status quo. If the first CGM measurement value Vcgm1corresponding to the first timing Tm1 posterior to the second timing Tm2in time-series is larger than the second CGM measurement value Vcgm2, itis because there is a high possibility that the glucose sensor 4 doesnot undergo the occurrence of the inconvenience such as thedeterioration. Incidentally, in the control example of FIG. 26, it doesnot happen that the first CGM measurement value Vcgm1 is equal to thesecond CGM measurement value Vcgm2 in terms of such a relation that theoperation proceeds to the process in step S506 if determined to beaffirmative in step S504. Alternatively, when determining that the firstCGM measurement value Vcgm1 is equal to or larger than the second CGMmeasurement value Vcgm2 (Vcgm1≧Vcgm2), as explained above, the settingvalue of the standby target setting temperature THb may be changed asthe process in step S508 instead of exiting the present routine.According to this scheme, the deterioration of the glucose sensor 4 canbe restrained more surely.

Further, the discussion has been made by exemplifying the case in whichthe monitoring device 1 according to the present embodiment periodicallymeasures the glucose concentration at the interval of the fixed periodof time continuously over, e.g., a few or several days through a few orseveral weeks, however, this example is no more than the preferableapplied example, and the present invention is not limited to thisexample. Moreover, the monitoring device 1 quantifies the subjectsubstance by measuring the glucose concentration in the body fluid,however, as in the case of determining whether or not the subjectsubstance exists in a fixed region peripheral to the sensor unit of theelectrochemical sensor or whether or not the subject substance exceeds acertain level, the present invention can be applied to evaluating thesubject substance qualitatively.

Furthermore, the subject substance in the body fluid is not limited tothe glucose but may be, e.g., lactic acid and other specifiedcomponents. In this case, the electrochemical sensor functions as alactic acid sensor for measuring a lactic acid level, and, e.g., alactic acid oxidase may be immobilized to the sensor unit (theimmobilized enzyme unit) thereof. Moreover, other preferable subjectsubstances can be exemplified such as bile acid. Furthermore, inaddition to the enzyme, a microorganism, an antibody and the cell can bepreferably applied as the living organism materials retained by thesensor unit of the electrochemical sensor. Further, the presentembodiment has discussed the example in which the present invention isapplied on the occasion of measuring the numerical value informationrelated to the subject substance in the body fluid of the person(examinee), however, body fluids of other subjects (e.g., animals otherthan the human being) may, as a matter of course, be used as thesamples.

The embodiments of the present invention have been discussed so far,however, the monitoring device, the monitoring system, the monitoringmethod, the program and the readable-by-computer recording mediumrecorded with the program are not limited to these embodiments, and thepresent invention can embrace combinations thereof to the greatestpossible degree.

1. A monitoring device which measures numerical value information on asubject substance in a body fluid, said device comprising: anelectrochemical sensor including a sensor unit for detecting the subjectsubstance which is used in the way of being embedded subcutaneously andgenerating an electric signal correlating to the numerical valueinformation on the subject substance; and a temperature control unitincluding a temperature sensor which measures a temperature correlatingto a detected ambient temperature defined as a temperature ambient tosaid sensor unit and a temperature adjusting element which adjusts thedetected ambient temperature, and adjusting the detected ambienttemperature so as to reach a target setting temperature when measuringthe subject substance by controlling an operation state of saidtemperature adjusting element on the basis of the temperature measuredby said temperature sensor.
 2. A monitoring device according to claim 1,further comprising a sensor control unit which controls saidelectrochemical sensor.
 3. A monitoring device according to claim 2,wherein said sensor control unit further calculates numerical valueinformation on the subject substance on the basis of an electric signalgenerated by said electrochemical sensor.
 4. A monitoring deviceaccording to claim 1, wherein said temperature control unit adjusts thedetected ambient temperature so as to reach a standby target settingtemperature that is set lower than the target setting temperature whenstanding by for measuring the subject substance.
 5. A monitoring deviceaccording to claim 1, wherein said temperature control unit acquiresfirst numerical value information defined as the numerical valueinformation on the subject substance measured by use of saidelectrochemical sensor and second numerical value information defined asthe numerical value information on the subject substance measured by asecond monitoring device in a way that uses a body fluid sampled invitro from an examinee, and changes, if a difference between the firstnumerical value information and the second numerical value informationexceeds a predetermined first threshold value, a setting value of thetarget setting temperature when measuring the subject substance.
 6. Amonitoring device according to claim 1, wherein said temperature controlunit adjusts the detected ambient temperature so as to reach a standbytarget setting temperature set lower than the target setting temperaturewhen standing by for measuring the subject substance, then acquiresfirst numerical value information defined as the numerical valueinformation on the subject substance measured by use of saidelectrochemical sensor and second numerical value information defined asthe numerical value information on the subject substance measured by asecond monitoring device in a way that uses the body fluid sampled invitro from the examinee, and changes, if the difference between thefirst numerical value information and the second numerical valueinformation exceeds a predetermined second threshold value, a settingvalue of the standby target setting temperature, on a low-temperatureside, when standing by for measuring the subject substance.
 7. Amonitoring device according to claim 1, wherein said temperature controlunit acquires, with respect to first numerical value information definedas the numerical value information on the subject substance measured byuse of said electrochemical sensor and second numerical valueinformation defined as the numerical value information on the subjectsubstance measured by a second monitoring device in a way that uses thebody fluid sampled in vitro from the examinee, each of the numericalvalue information corresponding to first timing after said monitoringdevice has started the measurement and the numerical value informationcorresponding to second timing that traces back to just a predeterminedperiod from the first timing, and changes, if a difference between thesecond numerical value information at the first timing and the secondnumerical value information at the second timing is within apredetermined third threshold value and if a difference between thefirst numerical value information at the first timing and the firstnumerical value information at the second timing exceeds a predeterminedfourth threshold value, a setting value of the target settingtemperature when measuring the subject substance.
 8. A monitoring deviceaccording to claim 1, wherein said temperature control unit acquires,with respect to first numerical value information defined as thenumerical value information on the subject substance measured by use ofsaid electrochemical sensor and second numerical value informationdefined as the numerical value information on the subject substancemeasured by a second monitoring device in a way that uses the body fluidsampled in vitro from the examinee, each of the numerical valueinformation corresponding to first timing after said monitoring devicehas started the measurement and the numerical value informationcorresponding to second timing that traces back to just a predeterminedperiod from the first timing, then adjusts the detected ambienttemperature so as to reach a standby target setting temperature that isset lower than the target setting temperature when standing by formeasuring the subject substance, and changes, if an elapse periodreaching the first timing since the start of the measurement exceeds apredetermined reference period, a setting value of the standby targetsetting temperature, on the low-temperature side, when standing by formeasuring the subject substance.
 9. A monitoring method by which amonitoring device comprising an electrochemical sensor including asensor unit, for detecting a subject substance in a body fluid, disposedin the way of being embedded subcutaneously, measures numerical valueinformation on the subject substance, said method comprising: a step ofadjusting a detected ambient temperature defined as a temperatureambient to said sensor unit so as to reach a target setting temperaturewhen measuring the subject substance.
 10. A monitoring method accordingto claim 9, further comprising: a temperature acquiring step ofacquiring a measurement result of a temperature sensor which measures atemperature correlating to the detected ambient temperature defined asthe temperature ambient to said sensor unit when measuring the subjectsubstance; a determining step of comparing the acquired temperatureacquired in said temperature acquiring step with a target settingtemperature and determining whether a temperature difference between theacquired temperature and the target setting temperature is within aspecified range or not; and a control step of controlling, whendetermining in said determining step that the temperature differenceexceeds the specified range, an operation state of a temperatureadjusting element for adjusting the detected ambient temperature so asto get approximate to the target setting temperature, wherein thedetected ambient temperature when detecting the subject substance isadjusted, and said monitoring method further comprises a calculationstep of calculating, when determining in said determining step that thetemperature difference between the acquired temperature and the targetsetting temperature is within the specified range, numerical valueinformation on the subject substance on the basis of an electric signalgenerated by said electrochemical sensor.
 11. A monitoring methodaccording to claim 10, wherein the detected ambient temperature isadjusted so as to reach a standby target setting temperature that is setlower than the target setting temperature when standing by for measuringthe subject substance.
 12. A monitoring method according to claim 10,wherein first numerical value information defined as the numerical valueinformation on the subject substance calculated in said calculation stepand second numerical value information defined as the numerical valueinformation on the subject substance measured in a way that uses a bodyfluid sampled in vitro from an examinee are acquired, and, if adifference between the first numerical value information and the secondnumerical value information exceeds a predetermined first thresholdvalue, a setting value of the target setting temperature when measuringthe subject substance is changed.
 13. A monitoring method according toclaim 10, wherein the detected ambient temperature is adjusted so as toreach a standby target setting temperature set lower than the targetsetting temperature when standing by for measuring the subjectsubstance, then first numerical value information defined as thenumerical value information on the subject substance calculated in saidcalculation step and second numerical value information defined as thenumerical value information on the subject substance measured in a waythat uses the body fluid sampled in vitro from the examinee areacquired, and if the difference between the first numerical valueinformation and the second numerical value information exceeds apredetermined second threshold value, a setting value of the standbytarget setting temperature when standing by for measuring the subjectsubstance is changed on a low-temperature side.
 14. A monitoring methodaccording to claim 10, wherein with respect to first numerical valueinformation defined as the numerical value information on the subjectsubstance calculated in said calculation step and second numerical valueinformation defined as the numerical value information on the subjectsubstance measured in a way that uses the body fluid sampled in vitrofrom the examinee, there is acquired each of the numerical valueinformation corresponding to first timing after said monitoring devicehas started the measurement and the numerical value informationcorresponding to second timing that traces back to just a predeterminedperiod from the first timing, and if a difference between the secondnumerical value information at the first timing and the second numericalvalue information at the second timing is within a predetermined thirdthreshold value and if a difference between the first numerical valueinformation at the first timing and the first numerical valueinformation at the second timing exceeds a predetermined fourththreshold value, a setting value of the target setting temperature whenmeasuring the subject substance is changed.
 15. A monitoring methodaccording to claim 10, wherein with respect to first numerical valueinformation defined as the numerical value information on the subjectsubstance calculated in said calculation step and second numerical valueinformation defined as the numerical value information on the subjectsubstance measured in a way that uses the body fluid sampled in vitrofrom the examinee, there is acquired each of the numerical valueinformation corresponding to first timing after said monitoring devicehas started the measurement and the numerical value informationcorresponding to second timing that traces back to just a predeterminedperiod from the first timing, then the detected ambient temperature isadjusted so as to reach a standby target setting temperature that is setlower than the target setting temperature when standing by for measuringthe subject substance, and if an elapse period reaching the first timingsince the start of the measurement exceeds a predetermined referenceperiod, a setting value of the standby target setting temperature whenstanding by for measuring the subject substance is changed on thelow-temperature side.